bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2026–07–19
forty-two papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Myonuclear Dynamics After Skeletal Muscle Surgical Injury.
  2. Reduced LANCL1-AS1 in old human skeletal muscle diminishes mitochondrial activity, shortens mt-mRNA poly(A) tails, and suppresses myogenesis.
  3. Muscle Satellite Cells and Aging.
  4. iPLA2β: A novel store-operated calcium entry modulator contributing to muscle dysfunction during denervation.
  5. Ageing alters cysteine oxidation-regulated redox signalling in skeletal muscle: Integrative omics and AI-based structural predictions.
  6. CaMKIIγ/δ contributes to mitochondrial metabolic adaptation in skeletal muscle during endurance training.
  7. Fibroblasts impair muscle stem cell self-renewal via excessive fibronectin deposition in viscoelastic hydrogel co-cultures.
  8. Mitochondrial transplantation and neuromuscular recovery after skeletal muscle injury.
  9. Sex-divergent skeletal muscle remodeling emerges early in cancer cachexia.
  10. Inactivation of SERCA2 at Cys674 induces skeletal muscle atrophy by activating the TGFβ/Smad-S100a4 axis to promote inflammation.
  11. Multifactorial nature of anabolic resistance in ageing skeletal muscle: A systems modelling study.
  12. Two-Way Communication Between Skeletal Muscle and Myokines.
  13. New Insights into Skeletal Muscle Metabolism in Pathological and Physiological Conditions: A Multidisciplinary and Translational Approach.
  14. Sex differences in metabolic remodeling and skeletal muscle regeneration following cardiotoxin-induced injury.
  15. Pediatric cancer therapy and skeletal muscle growth: An emerging role for satellite cell disruption.
  16. Spatiotemporal control of myonuclear identity during muscle regeneration.
  17. Selective targeting of skeletal muscle resident fibro-adipogenic progenitors via recombinant adeno-associated viral delivery.
  18. The Secretome of a Cachexia-Inducing Lung Tumor Impairs Mitochondrial Function and Skeletal Muscle Differentiation.
  19. Decoding the decline of postmenopausal skeletal muscle.
  20. Large increases in resistance training volume do not impair muscle hypertrophy or anabolic-catabolic molecular signaling in trained individuals.
  21. Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.
  22. Microgravity-Induced Muscle Atrophy in Rodent and Human Models‡.
  23. Dysregulation of the Schwann cell GABAergic system and Aβ-fibers conduction abnormalities in the sciatic nerve of the mdx mouse model of Duchenne muscular dystrophy.
  24. PPMO therapy for dysferlinopathy induces pseudoexon skipping and restoration of functional protein.
  25. Differential impact of cancer- and chemotherapy-induced cachexia: a comparative analysis in a pre-clinical model of colorectal cancer by biological sex.
  26. Aerobic Exercise Preserves Skeletal Muscle Function in Middle-Aged Mice Through the miR-150-5p/miR-199a-5p-Wnt/FZD4 Signaling Pathway.
  27. Mechanical Loading Induces Distinct and Shared Responses in Endothelial and Muscle Cells and Reveals Exercise-Like Molecular Profiles.
  28. ACL injury reprograms quadriceps myonuclear epigenetic and transcriptional signatures in mice.
  29. Intermittent time-restricted feeding improves physical performance and modulates mitochondrial morphology in a muscle fiber type dependent manner in middle-aged mice.
  30. UFC1 maintains ACSL3 abundance through UFMylation-associated mechanisms to modulate lipid metabolism in skeletal muscle myoblasts.
  31. Constitutive mTORC1 Activation in Skeletal Muscle Increases Inflammation but is not Sufficient to Impair Glucose Tolerance.
  32. Urolithin A enhances mitochondrial biogenesis-related markers and maximal respiratory capacity during C2C12 differentiation.
  33. Epigenetic Aging of Critical Illness Survivors Assessed by the Muscle-Specific "Clock" and Its Relationship With Reduced Long-Term Muscle Strength.
  34. PUF60 is a Critical Regulator of PKM Splicing During Myogenesis.
  35. The role of ABHD2 in cigarette smoke-induced skeletal muscle atrophy in chronic obstructive pulmonary disease mice: The mechanism of ABHD2 in skeletal muscle atrophy.
  36. Peroxisome Proliferator-Activated Receptor Delta Regulates Myogenic Differentiation via Lipid Droplet-Associated Metabolic Remodeling and p38 MAPK Signaling.
  37. TRIM72 alleviates skeletal muscle atrophy by modulating mt-dsRNA/RIG-I signaling.
  38. Understanding cachexia and muscle dysfunction in the context of metastatic breast cancer.
  39. Effectiveness of intermittent hypoxia on muscle recovery in rats: A systematic review.
  40. Use of organ transplant solution to preserve skeletal muscle for cellular and spatial transcriptomic analyses.
  41. Human umbilical cord-derived mesenchymal stem cells ameliorate muscle dysfunction and metabolic dysregulation in the CuZnSOD null mouse model of sarcopenia.
  42. Muscle Regeneration Failure May Lead to Clinical Features of Myopathy in Anti-IgLON5 Disease.
  1. FASEB J. 2026 Jul 31. 40(14): e72137
    Myonuclear Dynamics After Skeletal Muscle Surgical Injury.
    Micah Goeke, Nathan Serrano, Pieter Jan Koopmans, Kevin A Murach.
      A hallmark of damaged skeletal muscle fibers is displaced myonuclei that are no longer peripherally positioned. Displaced myonuclei are dogmatically thought to be derived exclusively from muscle stem cell (satellite cell) fusion. Using a surgical resection muscle injury model and in vivo recombination-independent "resident" (nonsatellite cell-derived) myonuclear labeling, we detail the prevalence, time course, and origin of displaced myonuclei in response to a nonchemically-mediated muscle trauma. We found that: (1) nonsatellite cell-derived (resident) displaced myonuclei emerge 7 days after surgical injury in similar proportion to exogenous (satellite cell-derived) displaced myonuclei, with a biased prevalence in myosin heavy chain IIB muscle fibers, (2) muscle fibers with multiple (≥ 2) displaced resident myonuclei in cross-section were an unexpected but noteworthy feature of muscle fibers 7 days after injury, (3) embryonic myosin-expressing fibers at 7 days postsurgery expectedly contain predominantly satellite cell-derived displaced myonuclei, but a subset have displaced resident myonuclei, and (4) satellite cell numbers in intact muscle do not increase until 7 days postsurgery. These data may help inform whether to target satellite cell-initiated processes, myonuclear-initiated processes, or both to facilitate muscle fiber injury repair. This information could lead to more effective therapeutic strategies for treating muscle trauma.
    Keywords:  damage; regeneration; satellite cells; surgery
    DOI:  https://doi.org/10.1096/fj.202602413R
  2. bioRxiv. 2026 Jul 06. pii: 2026.07.05.736613. [Epub ahead of print]
    Reduced LANCL1-AS1 in old human skeletal muscle diminishes mitochondrial activity, shortens mt-mRNA poly(A) tails, and suppresses myogenesis.
    Jen-Hao Yang, Elizabeth K Izydore, Krystyna Mazan-Mamczarz, Dimitrios Tsitsipatis, Julie A Mattison, Brigette Romero, Changyou Shi, Xiaoling Yang, Rachel Munk, Jennifer L Martindale, Carlos Anerillas, Martin Salamini-Montemurri, Martina Rossi, Yulan Piao, Jinshui Fan, Ya-Chen Chen, Bernardo Abel Cedeno-Veloz, Roberto Ferrero, Marta Montes, Nicolás Martínez-Velilla, Tian-Huei Chu, Kotb Abdelmohsen, Chang-Yi Cui, Mona Batish, Supriyo De, Payel Sen, Luigi Ferrucci, Rafael de Cabo, Myriam Gorospe.
      Regeneration of skeletal muscle preserves muscle mass and function, which decline with age. Here, we sought to identify long noncoding (lnc)RNAs involved in skeletal muscle myogenesis and potentially relevant to muscle aging. Cross-sectional analysis of skeletal muscle transcriptomes from healthy 22-through 89-year-old individuals revealed lncRNA LANCL1-AS1 among the top declining transcripts. Conversely, LANCL1-AS1 increased robustly during skeletal myogenesis and promoted myogenic differentiation in culture. Affinity pulldown by ChIRP followed by mass spectrometry revealed that LANCL1-AS1 associated with the mitochondrial protein LRPPRC, enhancing the formation of the chaperone complex LRPPRC-SLIRP, which maintains longer poly(A) tails of mitochondrial (mt-)mRNAs and stabilizes mt-mRNAs. Importantly, while myoblasts from old rhesus monkey muscle expressed lower levels of LANCL1-AS1 and mt-mRNAs, and displayed lower mitochondrial activity than young monkey myoblasts, overexpressing LANCL1-AS1 in old myoblasts restored mitochondrial activity and myogenesis. We propose that the age-associated reduction in LANCL1-AS1 contributes to impaired mitochondrial function and reduced myogenic capacity in aging skeletal muscle.
    DOI:  https://doi.org/10.64898/2026.07.05.736613
  3. Am J Physiol Cell Physiol. 2026 Jul 16.
    Muscle Satellite Cells and Aging.
    Amanda L Johnson, Ryan T Bevington, Samuel Rumelski, Natasha Kassamali, Gianni Parise.
      Aging is associated with a progressive decline in skeletal muscle mass and function, contributing to reduced physical capacity in older adults. Central is the deterioration of satellite cells, our tissue-resident muscle stem cells, which participate in adaptation, repair, and regeneration of skeletal muscle. Evidence from in vitro, murine, and human studies indicates an age-related reduction in satellite cell content, notably within type II muscle fibers, alongside impairments in myogenic potential. There is no single causative mechanism behind satellite cell age-related dysfunction, but a convergence of morphological changes and intrinsic and extrinsic factors that affect satellite cell dynamics and its niche. Intrinsic factors such as signalling pathways, cellular senescence, impaired autophagy, mitochondrial dysfunction, and epigenetic modifications can impact satellite cell function. Concurrently, extrinsic factors can impact the satellite cell niche and their function such as systemic circulating factors and vasculature and extracellular matrix remodeling. These age-related alterations can diminish regenerative capacity, blunt hypertrophic responses, and impair recovery from disuse or injury. Satellite cell dysfunction is a pivotal contributor to age-related skeletal muscle decline, frailty, and the quality of life in older adults. Despite growing insights from in vitro and animal models, the key mechanistic changes that underlie human satellite cell dysfunction with age are not fully understood. Improved characterization of age-related satellite cell changes in humans is essential to preserving muscle health across the lifespan.
    Keywords:  Aging; Satellite cells; Skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00232.2026
  4. Sci Adv. 2026 Jul 17. 12(29): eaed1646
    iPLA2β: A novel store-operated calcium entry modulator contributing to muscle dysfunction during denervation.
    Hongyang Xu, Shylesh Bhaskaran, Jacob Brown, Luis Gustavo Oliveira de Sousa, Constantin Georgescu, Elizabeth Duggan, Kara Kneuper, Ashley Bell, Jessica Thomason, Andy Gamez-Rico, Bo Hagy, Victoria Tyrrell, Valerie B O'Donnell, Kenneth Humphries, Holly Van Remmen.
      Sarcopenia, the age-related loss of skeletal muscle mass and strength, is a major cause of frailty and disability, with neuromuscular denervation as a key contributor. Bioactive lipid mediators, including lipid hydroperoxides and oxylipins, contribute to denervation-induced muscle atrophy and dysfunction. Here, we identify calcium-independent phospholipase A2β (iPLA2β) as a novel regulator of store-operated calcium ion (Ca2+) entry (SOCE), a critical process for maintaining Ca2+ homeostasis via stromal interaction molecule 1 (STIM1) and Orai1 coupling in skeletal muscle. Using muscle-specific iPLA2β knockout (miPLA2βKO) mice, we show that iPLA2β interacts with STIM1-Orai1 coupling to modulate SOCE. Denervation elevates iPLA2β, hyperactivating SOCE and causing Ca2+ overload through oxidative impairment of regulators such as SERCA. iPLA2β deletion normalizes SOCE, preserves Ca2+ homeostasis, and protects against denervation-induced muscle mass (5%) and strength loss (50%). These findings reveal that iPLA2β may be a critical link between oxidative stress and Ca2+ dysregulation and a promising target for mitigating muscle dysfunction during denervation.
    DOI:  https://doi.org/10.1126/sciadv.aed1646
  5. Exp Physiol. 2026 Jul 11.
    Ageing alters cysteine oxidation-regulated redox signalling in skeletal muscle: Integrative omics and AI-based structural predictions.
    Ufuk Ersoy, Malcolm J Jackson.
      Ageing is associated with loss of skeletal muscle mass and strength (sarcopenia) and disrupted redox homeostasis. Redox signalling is essential for muscle adaptation, yet the mechanisms by which ageing disrupts cysteine-based regulation are poorly defined. The drivers of site-specific reactivity and signalling specificity in aged muscle remain unknown. Here, we interrogated the OxiMouse dataset to map age-related cysteine oxidation in skeletal muscle and, using AI, simulate oxidative modifications at key cysteine residues to predict structural and functional consequences for specific proteins. Ageing was found to remodel the redox landscape through selective oxidation of discrete cysteine residues, in a site-specific manner, even within the same protein. These findings support that ageing drives pathway-targeted modulation of protein function rather than a uniform, global oxidative shift. Moreover, age-related cysteine oxidation is not randomly distributed but appears to target interconnected protein networks involved in mitochondrial metabolic pathways, muscle function and proteostasis, indicating a coordinated remodelling in redox signalling as a hallmark of skeletal muscle ageing. To connect proteomic signatures to mechanisms, AlphaFold3 was used to simulate progressive cysteine oxidation and predict structural outcomes. Protein docking simulations were then performed using HADDOCK. This approach was applied to prioritise functionally important cysteines identified in the dataset. These results suggest that skeletal muscle ageing drives selective rewiring of physiologically relevant cysteine-based redox signalling networks. By integrating redox proteomics with AI-based structural simulation, this study provides a framework to prioritise key oxidation-sensitive cysteines, including within the 26S proteasome, as potential mechanistic nodes and intervention targets for sarcopenia.
    Keywords:  ageing; alphafold3; cysteine; proteomics; reactive oxygen species; skeletal muscle
    DOI:  https://doi.org/10.1113/EP093750
  6. Mol Metab. 2026 Jul 13. pii: S2212-8778(26)00103-1. [Epub ahead of print] 102419
    CaMKIIγ/δ contributes to mitochondrial metabolic adaptation in skeletal muscle during endurance training.
    Ryoka Tsukahara, Yasuo Kitajima, Yuka Ichihashi, Hikaru Iwase, Shun Ohki, Yusuke Sotomaru, Tomohiro Kurosaki, Yohei Kawano, Tomoharu Yasuda.
       BACKGROUND: Calcium/calmodulin-dependent protein kinase II (CaMKII) is activated in skeletal muscle with exercise, yet its physiological role in endurance training adaptation remains unclear. This study determined whether endogenous CaMKIIγ/δ in skeletal muscle is required for endurance training-induced metabolic remodeling and exercise adaptation.
    METHODS: We generated male skeletal muscle-specific CaMKIIγ/δ knockout (CaMKII mKO) mice and assessed muscle phenotype, exercise capacity, and training adaptation. Acute exercise-induced CaMKII activation was evaluated by phosphorylation status. Transcriptomic changes were analyzed by RNA sequencing before and after 4 weeks of treadmill endurance training. Mitochondrial protein abundance, ultrastructure, and bioenergetics were examined by immunoblotting, transmission electron microscopy, and Seahorse extracellular flux analysis in myotubes with acute CaMKIIγ/δ deletion.
    RESULTS: Acute treadmill exercise induced CaMKII phosphorylation in muscle without altering total CaMKII abundance. CaMKII mKO mice showed normal muscle mass, grip strength, and baseline performance. However, endurance training-induced improvement in running capacity was significantly blunted. Transcriptomic analyses revealed downregulation of oxidative phosphorylation and glycolytic gene programs in CaMKII-deficient muscle at baseline and after training. OXPHOS complex protein abundance was partially reduced at baseline and markedly reduced across complexes I-V after training. CaMKII deficiency increased ultrastructurally abnormal mitochondria without reducing mitochondrial number. Consistently, CaMKII-deficient myotubes showed lower absolute per-well oxygen consumption and extracellular acidification rates.
    CONCLUSIONS: In male mice, endogenous CaMKIIγ/δ in muscle is dispensable for baseline locomotor performance but essential for endurance training-induced metabolic remodeling and mitochondrial integrity. These findings support a role for CaMKII in linking contraction-induced calcium signaling to metabolic adaptation in muscle.
    Keywords:  CaMKII; Endurance training; Exercise adaptation; Mitochondrial metabolism; Oxidative phosphorylation; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.molmet.2026.102419
  7. bioRxiv. 2026 Jul 06. pii: 2026.07.03.736419. [Epub ahead of print]
    Fibroblasts impair muscle stem cell self-renewal via excessive fibronectin deposition in viscoelastic hydrogel co-cultures.
    Tze-Ling Chang, Tenaya K Vallery, Thea S Zlatkov, Bradley B Olwin, Kristi S Anseth.
      Muscle satellite cells (SCs) regenerate skeletal muscle, but their regenerative capacity declines with age, in part due to extracellular matrix (ECM) remodeling and aberrant fibroblast activation within the SC niche. In regenerating young mouse muscle, fibronectin remodeling is transient, whereas in aged mouse muscle, fibronectin remodeling is prolonged and disorganized. Fibroblasts in aged mice are activated, increasing fibronectin deposition and expressing elevated α-smooth muscle actin (αSMA), which negatively influence SC fate. We develop a viscoelastic hydrogel co-encapsulation system, enabling three-dimensional co-culture of intact myofibers with primary fibroblasts. Using this 3D co-culture system, we show that fibroblasts from young mice support SC quiescence and self-renewal, whereas fibroblasts from aged mice aberrantly activate SCs and promote their differentiation on myofibers isolated from either young or aged mice. Knocking down fibronectin ( Fn1 ) in fibroblasts from aged mice partially restores SC function, promoting quiescence and limiting differentiation. Using a novel 3D hydrogel co-culture system, we demonstrate that fibroblast-deposited fibronectin is a key age-associated regulator negatively affecting SC fate within the SC niche of aged mice.
    DOI:  https://doi.org/10.64898/2026.07.03.736419
  8. J Physiol. 2026 Jul 15.
    Mitochondrial transplantation and neuromuscular recovery after skeletal muscle injury.
    Sina Hadipour-Lakmehsari, Sara Al Mouaswas.
      
    Keywords:  injury; mitochondria; mitochondrial transplantation; skeletal muscle
    DOI:  https://doi.org/10.1113/JP291869
  9. Am J Physiol Cell Physiol. 2026 Jul 16.
    Sex-divergent skeletal muscle remodeling emerges early in cancer cachexia.
    Chris Karagiannis, Alastair A E Saunders, Rachel E Thomson, María Guillán-Fresco, Wayne X Du, Craig A Goodman, Paul Gregorevic.
      Cancer cachexia is characterised by progressive skeletal muscle wasting and dysfunction, yet the early events that precede overt muscle wasting remain poorly defined. Here, we utilised a time-coursed C26 carcinoma model in male and female mice to define the pre-cachectic transcriptomic, proteostatic, immune, and metabolic adaptations between sexes. Males progressed more rapidly to cachexia and exhibited earlier impairments in body composition and grip strength, with shifts in muscle fiber size distribution detectable prior to changes in muscle mass. Transcriptomic analysis of the tibialis anterior muscle identified >6,000 differentially expressed genes, with >60% showing sex-specific regulation at the pre-cachectic stage. Proteostasis pathways were transcriptionally altered in both sexes, however, global muscle protein synthesis was suppressed earlier in males, preceding both measurable muscle mass loss and robust induction of specific E3 ubiquitin ligases. Transcripts related to innate immunity were preferentially elevated in males and accompanied by increased infiltration of myeloid cells, while systemic immune profiles showed limited concordant changes. Females showed preferential enrichment of insulin resistance and metabolic remodeling pathways, accompanied by early impairment of insulin handling and reduced muscle glycogen content at severe cachexia. These results show that cachexia progression in this model is sexually dimorphic and skeletal muscle undergoes extensive remodeling before overt wasting. Males exhibit earlier functional decline and muscle immune remodeling, whereas females show earlier metabolic vulnerability with impaired insulin handling. These findings define sex-divergent pre-cachectic windows that may guide early biomarker discovery and therapeutic strategies aimed at preventing progression and improving quality of life in cancer patients.
    Keywords:  Cancer-cachexia; flow-cytometry; insulin-resistance; protein-metabolism; transcriptomics
    DOI:  https://doi.org/10.1152/ajpcell.00271.2026
  10. Redox Biol. 2026 Jul 13. pii: S2213-2317(26)00299-5. [Epub ahead of print]95 104300
    Inactivation of SERCA2 at Cys674 induces skeletal muscle atrophy by activating the TGFβ/Smad-S100a4 axis to promote inflammation.
    Fei Nan, Siyao Liu, Shunyi Lei, Yu Peng, Hailong Zhang, Xun Chen, Shixin Jin, Yuanfu Mao, Dan Lin, Xiaoyong Tong, Yanlong Qu.
       BACKGROUND & AIMS: Disuse-induced skeletal muscle atrophy is a major clinical challenge lacking effective targeted therapies. Sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) is essential for calcium homeostasis in skeletal muscle, but whether its C674 active site contributes to muscle atrophy remains unclear. This study investigated the role of SERCA2 C674 inactivation in skeletal muscle atrophy and the underlying mechanisms.
    METHODS: Oxidized SERCA2 (C674-SO3H) expression was assessed in atrophied muscles from bedridden patients and in a murine hindlimb suspension (HLS) model. A SERCA2 C674S knock-in (SKI) mouse model was generated to mimic irreversible oxidation in vivo. Transcriptomic and proteomic analyses, together with in vitro experiments in C2C12 myoblasts and in vivo interventions using Losartan or adeno-associated virus serotype 9 (AAV9)-mediated shRNA, were performed to define downstream signaling pathways and therapeutic potential.
    RESULTS: Total SERCA2 protein levels were unchanged in atrophied muscles from patients and HLS mice, whereas C674-SO3H expression was significantly increased. SKI mice developed spontaneous skeletal muscle atrophy, with reduced myofiber cross-sectional area and impaired muscle strength. Multi-omics analyses showed that SERCA2 dysfunction activated the renin-angiotensin system (RAS)-dependent TGF-β/Smad pathway and markedly upregulated S100a4. Mechanistically, S100a4 interacted with Smad3 and acted as a key downstream effector promoting oxidative stress, inflammation, and muscle protein degradation-related pathways. In vivo treatment with Losartan or AAV9-mediated S100a4 knockdown alleviated local inflammation, fibrosis, and muscle atrophy in both SKI and HLS mice.
    CONCLUSIONS: The oxidative inactivation of the SERCA2 C674 site constitutes a novel mechanism driving skeletal muscle atrophy. The SERCA2-RAS-TGF-β/Smad-S100a4 signaling axis emerges as a highly promising therapeutic target for mitigating disuse-induced skeletal muscle wasting.
    Keywords:  Inflammation; S100a4; SERCA2; Skeletal muscle atrophy; TGFβ/Smad signaling pathway
    DOI:  https://doi.org/10.1016/j.redox.2026.104300
  11. J Physiol. 2026 Jul 17.
    Multifactorial nature of anabolic resistance in ageing skeletal muscle: A systems modelling study.
    Taylor J McColl, Daniel R Moore, Eldon Emberly, David D Church, David C Clarke.
      Sarcopenia, the age-related loss of skeletal muscle mass and function, is primarily caused by anabolic resistance, which is the blunted stimulation of muscle protein synthesis (MPS) and impaired suppression of muscle protein breakdown following anabolic stimuli such as feeding. Multiple age-related impairments have been implicated, but none alone explains reduced MPS in older adults, suggesting that anabolic resistance arises from interacting dysregulated processes. Studying these interactions experimentally is challenging, motivating systems approaches. Here, we applied a mechanistic, multiscale kinetic model of leucine-mediated signalling and protein metabolism in human skeletal muscle to study anabolic resistance mechanisms. Parameter values were estimated from published data. Global sensitivity analysis identified key controllers of MPS and net protein balance (NB). Virtual population simulations of MPS responses to amino acid feeding were classified as anabolic sensitive or anabolic resistant. We quantified individual and combined age-related impairments and simulated therapeutic interventions to restore anabolic responsiveness. Sensitivity analyses revealed that intracellular signalling processes controlling MPS dominate NB. Feeding simulations indicated that dysregulation of these processes distinguished anabolic-sensitive from anabolic-resistant phenotypes. No single dysregulated mechanism reproduced age-related reductions in MPS. Instead, anabolic resistance emerged only when multiple impairments operated together. Restoring MPS from multifactorial dysregulation required co-ordinated, multitarget therapeutic strategies. These findings demonstrate that anabolic resistance arises from multiple interacting dysregulations in nutrient sensing and signalling. By quantifying their contributions in a systems framework, this work advances mechanistic understanding of sarcopenia and supports the design of combined interventions to restore muscle protein metabolism in older adults. KEY POINTS: Anabolic resistance is a key contributor to sarcopenia, but no single age-related physiological impairment fully explains the reduced muscle protein synthesis response observed in older adults. Systems modelling identified intracellular signalling processes that directly control muscle protein synthesis as dominant drivers of net protein balance, distinguishing anabolic-sensitive from anabolic-resistant phenotypes. Simulations reveal that anabolic resistance emerges from the combined effects of multiple dysregulated mechanisms rather than from single impairments acting independently. Clinically, interventions targeting single mechanisms are unlikely to fully restore muscle anabolism in older adults, particularly when multiple impairments coexist. Simulations predict combinations of age-related impairments that are most important to address to restore anabolic responsiveness, thereby informing multimodal therapeutic strategies for sarcopenia.
    Keywords:  anabolic resistance; computational biology; mathematical model; protein synthesis; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1113/JP290799
  12. Cell Biochem Funct. 2026 Jul;44(7): e70267
    Two-Way Communication Between Skeletal Muscle and Myokines.
    Tengteng Huang, Shihao Zhou, Xiaoling Chen, Daiwen Chen, Bing Yu, Zhiqing Huang.
      Myokines are defined as a class of bioactive molecules-including metabolites, peptides, and proteins-released from skeletal muscle cells and promoted by exercise. Recently, myokine-mediated muscle-organ crosstalk has sparked increased interest. Skeletal muscle secretes hundreds of myokines in an autocrine, paracrine, or endocrine manner, mediating the crosstalk between skeletal muscle and skeletal muscle itself, bone, fat, liver, and so on to regulate the physiological state of multiple organs, exerting a wide range of benefits of exercise. The relationship between muscle and myokines may be better understood as an exercise-responsive regulatory framework involving skeletal muscle and myokines, although direct evidence for an integrated bidirectional feedback network remains incomplete. In the network, myokines regulate skeletal muscle metabolism and remodeling through autocrine/paracrine actions, while exercise-induced muscle-derived signals may also contribute to long-lasting systemic adaptations involving immune mobilization, redox homeostasis, gut microbiota-related metabolic remodeling, and gut-muscle-bone crosstalk. Therefore, the distinct feature of skeletal muscle is not the mere presence of bidirectional signaling but its large mass, fiber-type metabolic heterogeneity, and direct responsiveness to repeated mechanical stimuli during exercise. On the one hand, as a source of myokines, the stimulation of skeletal muscle affects the production of myokines through various signaling pathways. On the other hand, myokines affect skeletal muscle function, such as glucose absorption, fatty acid oxidation, skeletal muscle mass, and muscle fiber type transformation. What's more, some myokines are muscle fiber type-specific, meaning that the expression of myokines may be influenced by muscle fiber type. Based on these, this review aims to summarize current evidence for exercise-responsive interactions between skeletal muscle and myokines and to identify where feedback regulation remains hypothetical.
    Keywords:  exercise; muscle fiber type; myokines; signaling pathway; skeletal muscle mass
    DOI:  https://doi.org/10.1002/cbf.70267
  13. Biology (Basel). 2026 Jul 01. pii: 1052. [Epub ahead of print]15(13):
    New Insights into Skeletal Muscle Metabolism in Pathological and Physiological Conditions: A Multidisciplinary and Translational Approach.
    Cristina Antinozzi, Paolo Sgrò, Luigi Di Luigi.
      Skeletal muscle represents not only the largest component of our total body mass but also functions as an endocrine and metabolic organ [...].
    DOI:  https://doi.org/10.3390/biology15131052
  14. Sci Rep. 2026 Jul 13.
    Sex differences in metabolic remodeling and skeletal muscle regeneration following cardiotoxin-induced injury.
    Jong Beom Jin, Tori Soukup, Angelique Robinson, Ember Black, Addison Williams, Atul Pranay, Kenneth Humphries, Dong Yeon Kim, Yoo Kim, Edralin Lucas, Shane M Hammer, Jiyoung Bae.
      Skeletal muscle regeneration is a dynamic biological process that requires metabolic remodeling, satellite cell activation, inflammatory responses, and tissue remodeling. Although biological sex is recognized as an important determinant of skeletal muscle regeneration, whether males and females utilize distinct metabolic programs during regeneration remains poorly understood. In the present study, we investigated sex-dependent differences in metabolic remodeling and regenerative responses following cardiotoxin (CTX)-induced skeletal muscle injury in mice. Targeted metabolomic analysis performed at 7 days post-injury (DPI) revealed clear sex-dependent metabolic remodeling. Principal component analysis and pathway enrichment analysis identified glycolysis/gluconeogenesis as the most significantly altered metabolic pathway following injury. Male mice exhibited higher levels of several glycolytic, tricarboxylic acid (TCA) cycle, and amino acid metabolites than female mice. In contrast, female mice showed greater expression of Pax7, Myf5, and Myod1, together with increased Pax7-positive cells, greater Cyclin D1 staining, and higher expression of Ccne1, Cdc2, and Cdk4. Local inflammatory responses also differed between sexes, with distinct temporal patterns of MCP-1, IL-6, TNF-α, and CD45 during regeneration. Histological analyses demonstrated greater lipid accumulation in female muscle at 7 DPI, whereas both sexes exhibited comparable percentages of centrally nucleated fibers and similar restoration of muscle architecture by 21 DPI. Together, these findings indicate that biological sex is associated with differences in metabolism, satellite cell-associated responses, inflammatory responses, and tissue remodeling during skeletal muscle regeneration. Although males and females ultimately achieved comparable structural recovery, the regenerative process differed substantially during the early phase after injury. These findings provide additional insight into the biological processes underlying sex-dependent skeletal muscle regeneration and establish a foundation for future studies investigating the mechanisms linking metabolism to regeneration.
    Keywords:  Glycolysis; Metabolomics; Sex differences; Skeletal muscle regeneration
    DOI:  https://doi.org/10.1038/s41598-026-62000-9
  15. Am J Physiol Cell Physiol. 2026 Jul 14.
    Pediatric cancer therapy and skeletal muscle growth: An emerging role for satellite cell disruption.
    Cory M Dungan, Rachel R Chiella, Saji Tabrizi, Joe V Chakkalakal, Michael P Wiggs.
      Improvements in pediatric cancer survival has increased the risk of long-term, treatment-related complications, including persistent skeletal muscle deficits. These impairments are often interpreted through mechanisms derived from adult models, which emphasize mitochondrial dysfunction and metabolic stress. However, pediatric cancer therapies are delivered during periods of active growth, when skeletal muscle expansion depends on satellite cell-mediated myonuclear accretion and establishment of the adult stem cell pool. In this Perspective, we propose that radiation and chemotherapy disrupt satellite cell-dependent processes during development, leading to impaired muscle growth and long-term functional deficits. Evidence from radiation models demonstrates reduced satellite cell abundance, impaired regeneration, and persistent structural abnormalities throughout pediatric development, while emerging chemotherapy data indicate alterations in myogenic regulatory programs and reduced satellite cell number, with limited overlap with adult responses. Together, these findings support a framework in which pediatric cancer therapies impair developmental muscle growth rather than solely inducing atrophy. Targeting satellite cells may represent a therapeutic strategy to restore muscle development and improve long-term outcomes in pediatric cancer survivors.
    Keywords:  Cancer survivorship; chemotherapy toxicity; developmental muscle biology; muscle regeneration; myonuclear accretion
    DOI:  https://doi.org/10.1152/ajpcell.00304.2026
  16. Curr Opin Genet Dev. 2026 Jul 16. pii: S0959-437X(26)00083-3. [Epub ahead of print]100 102516
    Spatiotemporal control of myonuclear identity during muscle regeneration.
    Minchul Kim, Yu Xin Wang, Nour El Khazen.
      Skeletal muscle exhibits an unusually complex architecture, in which large multinucleated myofibers accommodate a small population of resident muscle stem cells (MuSCs) along their surface. In addition, myofibers contain molecularly and functionally specialized domains at junctions with motor neurons and tendons. Regeneration of this tissue, therefore, requires a coordinated series of events, spanning MuSC activation, proliferation, fusion to restore myofiber mass, as well as reconstruction of specialized domains. Recent advances have begun to reveal how myogenic nuclei undergo dynamic state transitions in response to interactions with surrounding cell types, and how these states can be remodeled during regeneration. Here, we discuss emerging principles of myonuclear plasticity and spatial specialization.
    DOI:  https://doi.org/10.1016/j.gde.2026.102516
  17. Sci Rep. 2026 Jul 12.
    Selective targeting of skeletal muscle resident fibro-adipogenic progenitors via recombinant adeno-associated viral delivery.
    Yangyi E Luo, Elisabeth R Barton.
      Fibro-Adipogenic Progenitors (FAPs) are muscle-resident mesenchymal stromal cells that are essential for skeletal muscle regeneration, but also drive pathological fibrosis and adiposity. FAP properties have been modulated by transgenic strategies, but the field lacks an efficient tool for specific, localized, in vivo FAP targeting. Adeno-Associated Viruses (AAVs) have become a standard for delivery of transgenes with both natural and engineered cell specificity for uptake, or tropism. The goal of this study was to develop an AAV system with FAP specificity. We isolated the promoter for murine platelet derived growth factor receptor alpha (Pdgfra), a FAP-specific marker, to drive expression of the reporter, ZsGreen. Cell transfection confirmed that full-length (2.2 kb) and truncated (826 bp) promoters restricted expression to FAPs, with the 826 bp sequence providing higher gene expression. Next, we compared AAV5 and AAV8 serotypes, packaging each promoter sequence versus the CMV promoter or to no vector. Following intramuscular AAV injection (1 × 1011vg/TA), immunofluorescence and cell-sorting revealed that AAV5 harboring the 826 bp Pdgfra promoter provided optimal FAP specificity and expression level. Importantly, minimal off-target expression in myofibers or other mononucleated populations, including endothelial, immune, and satellite cells was found. These results demonstrate the development of an AAV-based tool for precise, in vivo manipulation of FAPs.
    Keywords:  Fibro-Adipogenic Progenitors; platelet derived growth factor receptor alpha (Pdgfra); viral gene delivery
    DOI:  https://doi.org/10.1038/s41598-026-59253-9
  18. Cancers (Basel). 2026 Jun 30. pii: 2130. [Epub ahead of print]18(13):
    The Secretome of a Cachexia-Inducing Lung Tumor Impairs Mitochondrial Function and Skeletal Muscle Differentiation.
    Nikki Wanders, Marvin Martens, Marco Kelders, Sven Manse, Sandra van Krimpen, Claire Groenen, Chrysi Kapsali, Paula Bilbao Fraile, Konstantina Bermperi, Niels Boumans, Youssra Ahidar, Ludwig Dubois, Hubert Smeets, Wouter van de Worp, Ramon Langen.
      Background: Cancer-associated cachexia (CAC) can affect up to 80% of patients with late-stage cancer and is characterized by depletion of skeletal muscle mass with or without loss of fat tissue. No effective treatments are currently available, and reversing CAC requires understanding the intracellular processes of muscle atrophy and its cancer-related extracellular triggers. In this study, we aimed to disentangle tumor- and host-driven mechanisms in CAC muscle wasting. Methods: In skeletal muscle tissue obtained from control non-tumor-bearing mice and cachectic mice resulting from orthotopically implanted 344P lung adenocarcinoma cells, transcriptomic analyses were performed to identify muscle wasting-associated processes. To explore whether these reflected direct tumor-induced effects, 344P tumor-conditioned medium (tCM) was applied to in vitro cultured C2C12 skeletal muscle cells to investigate the impact on muscle proteolysis, myogenesis and mitochondrial function. Results: RNAseq data revealed increased proteolysis along with decreased myogenesis-related processes, and prominent downregulation of genes encoding mitochondrial OXPHOS complexes, in cachectic mouse muscle. Exposure of cultured skeletal muscle cells to tCM reduced mitochondrial respiration and induced changes in mitochondrial mass and mitochondrial DNA copy number. tCM did not induce myotube atrophy, or activation of proteolysis-related signaling, in fully differentiated myotubes. In contrast, tCM reversibly inhibited myoblast-myotube fusion, and reduced myogenic and muscle-specific gene expression in differentiating myoblasts. Application of CCCP to simulate muscle mitochondrial dysfunction reproduced the myogenesis-impairing phenotype caused by tCM. Conclusions: Our results show that factors present in the cachexia-inducing lung tumor secretome directly impair myogenesis and muscle mitochondrial function, whereas activation of muscle catabolic processes requires host-dependent mechanisms.
    Keywords:  C2C12; cachexia; lung adenocarcinoma; muscle wasting
    DOI:  https://doi.org/10.3390/cancers18132130
  19. Physiol Genomics. 2026 Jul 13.
    Decoding the decline of postmenopausal skeletal muscle.
    Glen Pyle.
      
    Keywords:  biomarkers; genomics; menopause; perimenopause; skeletal muscle
    DOI:  https://doi.org/10.1152/physiolgenomics.00048.2026
  20. J Appl Physiol (1985). 2026 Jul 16.
    Large increases in resistance training volume do not impair muscle hypertrophy or anabolic-catabolic molecular signaling in trained individuals.
    Júlio B B Camargo, Diego Bittencourt, J Max Michel, Deivid G Silva, João G A Bergamasco, Alexander C Berry, Dakota R Tiede, Dustyn Lewis, Enya T A Nacafucasaco, Otávio Ferrari, Ana C C Melo, Matheus Iasulaitis, Marcelo Rebelatto, Michael D Roberts, Cleiton A Libardi.
      Skeletal muscle hypertrophy results from the integrated regulation of anabolic and proteolytic processes in response to mechanical loading. Although increases in resistance training (RT) volume are used to increase mechanical stress, it remains uncertain whether large and abrupt volume progressions could exceed muscle adaptive capacity by disrupting the balance between anabolic and catabolic signaling. The present study investigated whether a large increase in weekly RT volume (+120%) leads to impaired hypertrophic outcomes and intracellular regulatory responses compared with a modest increase (+20%). Twenty-five resistance-trained men and women (18-35 years old) completed an 8-week randomized, single-blind, within-subject unilateral intervention. Each participant trained both legs twice weekly, with one leg assigned to the large (VOL120) and the contralateral leg to the modest (VOL20) weekly volume progressions relative to habitual training volume. Vastus lateralis muscle cross-sectional area (mCSA) was assessed by ultrasonography before and after training. Muscle biopsies were obtained at baseline, post-intervention, and 24 h after the last session to quantify muscle fiber cross-sectional area (fCSA), satellite cell myonuclear content, and anabolic/catabolic signaling markers. Both protocols induced increases in mCSA over time (p<0.001), with no protocol vs. time interaction. No significant effects were observed for fCSA nor satellite cell number or myonuclear content. Additionally, molecular responses related to translational regulation and protein degradation were largely similar between protocols. A large abrupt increase in weekly resistance training volume (+120%) did not attenuate muscle hypertrophy relative to a modest increase (+20%) in resistance-trained individuals, and most acute and chronic molecular markers assessed likewise did not differ significantly between protocols.
    Keywords:  exercise; muscle adaptation; protein synthesis; skeletal muscle fiber; training
    DOI:  https://doi.org/10.1152/japplphysiol.00284.2026
  21. Mol Metab. 2026 Jul 17. pii: S2212-8778(26)00106-7. [Epub ahead of print] 102422
    Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.
    Emma Frank, Kaspar W Persson, Pauline Morigny, Zakarias Kefil Jensen Ogueboule, Tang Cam Phung Pham, Jonas R Knudsen, Maria Rohm, Lykke Sylow, Steffen H Raun.
       PURPOSE: Cancer cachexia is a life-threatening complication of advanced malignancies, driven by profound systemic metabolic reprogramming and anorexia. Insulin action is markedly impaired in patients with cancer and may contribute directly to cachexia pathogenesis. However, the interplay between weight loss, food intake, and cancer-associated metabolic rewiring in cachexia remains poorly defined. Clarifying this relationship is essential for identifying the fundamental drivers of cachexia and for developing effective therapeutic strategies.
    METHODS: We assessed metabolic rewiring by temporal evaluation of glucose tolerance and isotopic tracers to determine muscle insulin-stimulated glucose uptake in male cachectic and non-cachectic C26- and KPC-tumor-bearing, as well as healthy mice undergoing food restriction.
    RESULTS: Cachectic C26- and KPC-tumor mice showed increased glucose tolerance compared to non-tumor-bearing control mice, and non-cachectic tumor-bearing mice. Increased glucose tolerance appeared prior to overt muscle loss, independent of tumor size and changes in food intake. Ex vivo insulin-stimulated glucose uptake was elevated in soleus (+78%) and extensor digitorum longus (+35%) muscle from cachectic C26-cancer mice with anorexia compared to weight stable C26-cancer mice and control mice. This increase was associated with enhanced AKT signaling. Food restriction in healthy mice increased glucose tolerance, insulin-stimulated glucose uptake ex vivo, and AKT signaling.
    CONCLUSIONS: Our findings suggest that glucose hypermetabolism appears prior to overt weight loss in pre-clinical cachexia, whereas late-stage cachexia with anorexia increased skeletal muscle insulin responsiveness. This highlights AKT signaling as a key node connecting nutrient status with muscle metabolism in cancer cachexia.
    Keywords:  Cancer cachexia; food restriction; glucose metabolism; insulin sensitivity; muscle
    DOI:  https://doi.org/10.1016/j.molmet.2026.102422
  22. Free Radic Biol Med. 2026 Jul 15. pii: S0891-5849(26)00959-7. [Epub ahead of print]
    Microgravity-Induced Muscle Atrophy in Rodent and Human Models‡.
    Eileen Y Su, Samantha Jones, Benjamin R Tollitt, Anne McArdle, Lisa M Larkin.
      Exposure to microgravity leads to severe skeletal muscle atrophy, particularly in muscles that act to maintain posture against gravity, and results in significant reductions in muscle mass, cross-sectional area, and contractile force. This review examines the physiological and cellular response of microgravity in both rodent and human models, emphasizing shifts in muscle fiber type, altered contractile properties, and molecular adaptations. Specifically, rodents exhibit rapid atrophy, predominantly in slow-twitch fibers, whereas human studies suggest greater intersubject variability, with both slow- and fast-twitch fibers significantly affected. Cellular responses due to microgravity reveal mitochondrial dysfunction, oxidative stress, and impaired synaptogenesis as key contributors to muscle degradation. Further, despite exercise countermeasures, spaceflight induced atrophy remains a significant challenge. Understanding these mechanisms is crucial for developing therapeutics to mitigate musculoskeletal degradation during prolonged spaceflight. The aim of this review is to compare the effects of microgravity-induced skeletal muscle atrophy across rodent, human, and in vitro models, highlight species differences in responses, and evaluate Reactive Oxygen Species (ROS)-mediated mechanisms that underlie muscle loss throughout spaceflight.
    Keywords:  Microgravity; Mitochondria; Muscle Atrophy; ROS; Skeletal Muscle
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.032
  23. Neurobiol Dis. 2026 Jul 16. pii: S0969-9961(26)00279-2. [Epub ahead of print] 107534
    Dysregulation of the Schwann cell GABAergic system and Aβ-fibers conduction abnormalities in the sciatic nerve of the mdx mouse model of Duchenne muscular dystrophy.
    Silvia Di Nuzzo, Francesca Mastrostefano, Marzia Soligo, Tasnim Mohamed, Veronica Bonalume, Eleonora De Santis, Francesca Grassi, Valentina Ferretti, Ada Maria Tata, Valerio Magnaghi, Maria Egle De Stefano.
      Duchenne muscular dystrophy (DMD), a lethal X-linked disorder caused by loss of the full-length dystrophin Dp427, is characterized by progressive skeletal muscle degeneration, although increasing evidence indicates a broader neuromuscular dysfunction. Here, we identify impaired Schwann cell (SC) homeostasis in the sciatic nerve of dystrophic mdx mice. Integrated molecular, immunofluorescence, ultrastructural, and electrophysiological analyses demonstrate that sciatic nerves from 6 to 7-week-old mdx mice exhibit downregulation of key myelin proteins (MBP, P0, PMP22), compared with age-matched wild type mice. Despite preserved SC dystrophin isoforms (Dp116 and Dp71), core components of the dystrophin-associated glycoprotein complex (DGC), namely α- and β-dystroglycan and dystrobrevin, are significantly reduced. Concomitant activation of matrix metalloproteinases (MMP)-2 and MMP-9 is consistent with enhanced proteolytic processing and DGC destabilization. These alterations are accompanied by reduced mRNA and protein expression of GABA-A and GABA-B receptors and the GABA-synthesizing enzymes GAD65 and GAD67, indicating perturbed autocrine/paracrine GABAergic signaling at the SC-axon interface, further supported by altered neuregulin-1/ErbB2 signaling. Furthermore, sensory Aβ-fibers from mdx mice exhibit mild hypoexcitability, altered refractoriness, and impaired tolerance to high-frequency stimulation, consistent with impaired myelin integrity and diminished electrical insulation, confirmed by ultrastructural evidence of focal myelin abnormalities affecting a subset of nerve fibers. Notably, none of the parameters examined in 10-day-old mdx mice showed detectable alterations, suggesting that sciatic nerve abnormalities become evident after the onset of overt muscle degeneration. Altogether, these findings identify the sciatic nerve as a previously underappreciated site of disease-associated alterations in DMD and a potential target for future therapeutic investigations.
    Keywords:  Duchenne muscular dystrophy; GABA receptors; Myelin; Schwann cells; Sciatic nerve
    DOI:  https://doi.org/10.1016/j.nbd.2026.107534
  24. JCI Insight. 2026 Jul 14. pii: e204742. [Epub ahead of print]
    PPMO therapy for dysferlinopathy induces pseudoexon skipping and restoration of functional protein.
    James E Gooding, Gyeongsu Park, Atish Wagh, Jonathan K Watts, Janice A Dominov, Robert H Brown.
      The dysferlinopathies are a spectrum of autosomal recessive muscle diseases caused by mutations in the dysferlin gene (DYSF) gene. Clinical manifestations vary from asymptomatic hyperCKemia to severe muscle pathology and loss of muscle function. These are designated limb-girdle muscular dystrophy type 2R or LGMDR2 (formerly LGMD2B or Miyoshi myopathy). Among other functions, dysferlin is crucial for plasma membrane repair and maintenance of intracellular calcium homeostasis. In previous studies, we identified in two independent point mutations deep within introns that cause aberrant DYSF mRNA splicing and the inclusion of pseudoexons within transcripts that disrupt protein expression. In this study, we generated and characterized a novel mouse model for one of these mutations (within DYSF intron 44). In these mice, a segment of human DYSF DNA containing the mutant intronic sequence flanked by surrounding human exon sequences replaces the normal homologous mouse DNA. These mice exhibit aberrant Dysf pre-mRNA splicing, pseudoexon inclusion, loss of DYSF protein expression, and muscle pathology similar to that observed in patients. Using this new model, we identified antisense oligonucleotides and then a PPMO that blocks the mouse Dysf pre-mRNA splicing complexes from binding the mutant pre-mRNA, thereby restoring nearly normal muscle histology and function.
    Keywords:  Gene therapy; Genetic diseases; Genetics; Muscle biology; Skeletal muscle
    DOI:  https://doi.org/10.1172/jci.insight.204742
  25. Am J Physiol Endocrinol Metab. 2026 Jul 15.
    Differential impact of cancer- and chemotherapy-induced cachexia: a comparative analysis in a pre-clinical model of colorectal cancer by biological sex.
    Ana Regina Cabrera, Eleanor R Schrems, Ruqaiza Muhyudin, Francielly Morena, Stavroula Tsitkanou, Ronald G Jones, Kaitlyn Parker, Morghan Relich, Kevin A Murach, Timothy J Muldoon, Tyrone A Washington, Nicholas P Greene.
      Cancer cachexia is a wasting condition characterized by muscle loss and reduced quality of life in cancer patients. Although biological sex differences in the progression of cancer cachexia have been increasingly recognized, their role during chemotherapy-treated cancer cachexia remains largely unexplored. We evaluated such potential differences using male and female mice implanted subcutaneously with Colon-26 allografts. Our novel approach to disentangle the effects of chemotherapy consisted of administering two cycles of 75% of the maximum tolerated dose of 5-fluorouracil, cisplatin, or paclitaxel, in the presence and absence of cancer (n=6-11/condition). Muscles and organs were collected 25 days following tumor implant, and protein turnover markers, gene expression through RNA sequencing, and mitochondrial function were evaluated in gastrocnemius. A two-way factorial analysis was conducted to assess main effects and interactions across groups (p<0.05). We demonstrate chemotherapy exhibited preserved fat mass in males while maintained body weight in females. Chemotherapy elicited negative impacts on muscle in both sexes, even in a reduced or absent tumor burden. In males, protein synthesis was lower in the presence of cancer and chemotherapy without corresponding differences in atrogenes. Cluster analysis revealed largest differences in muscle transcriptome between cancer control and C26-paclitaxel in male mice, highlighting altered regulation of ubiquitin-mediated proteolysis. These findings point to divergent mechanisms during protein processing in endoplasmic reticulum regulation in muscle atrophy associated with cancer in the presence of chemotherapy. Our results highlight distinct mechanisms underlying cancer-cachexia alone versus the addition of chemotherapy and further indicate responses to chemotherapy differ between biological sexes.
    Keywords:  5-fluorouracil; Atrophy; Cisplatin; Muscle loss; Paclitaxel; Protein Processing; Skeletal muscle
    DOI:  https://doi.org/10.1152/ajpendo.00131.2026
  26. Biology (Basel). 2026 Jun 25. pii: 1001. [Epub ahead of print]15(13):
    Aerobic Exercise Preserves Skeletal Muscle Function in Middle-Aged Mice Through the miR-150-5p/miR-199a-5p-Wnt/FZD4 Signaling Pathway.
    Le Zhang, Jingzi He, Li Wang, Huan Zhang.
      MicroRNAs are important regulators of skeletal muscle development and regeneration; however, the molecular basis by which exercise-induced miRNAs preserve middle-aged muscle function remains to be elucidated. This study aimed to investigate how aerobic exercise delays skeletal muscle attenuation by reversing age-related miRNAs dysregulation in male mice. Twelve-month-old male C57BL/6J mice (MC) (n = 8/group) were randomly assigned to a sedentary control group (OC) or an aerobic exercise group (OE) (12 m/min, 40 min/session, three sessions/week, for 12 weeks). miRNA sequencing identified differentially expressed miRNAs (DEmiRNAs), followed by miRNA-mRNA network construction. The results demonstrated that aerobic exercise improved muscle strength and mass while attenuating early atrophy and fibrosis. Four atrophy-associated DEmiRNAs (miR-150-5p, miR-199a-5p, miR-3535, and miR-329-5p) were reversed after aerobic exercise intervention. GO and KEGG profiling demonstrated that target genes were predominantly involved in protein binding and the Wnt signaling pathway. miR-199a-5p and miR-150-5p, with the most predicted targets, were selected as candidate mechanistic contributors, and FZD4 was confirmed as a common downstream target. Further analysis confirmed that miR-199a-5p and miR-150-5p inhibition attenuated D-galactose-induced C2C12 myotube atrophy, reducing Atrogin-1 and increasing MyoD1, FZD4, and β-catenin expression. These findings suggest that the exercise-induced miR-150-5p/miR-199a-5p axis may alleviate muscle aging in middle age via the restoration of key proteins in Wnt signaling and contribute preliminary observational evidence relevant to the understanding of aerobic exercise intervention in sarcopenia.
    Keywords:  aerobic exercise; miR-150-5p; miR-199a-5p; miRNA-seq; middle-aged; sarcopenia
    DOI:  https://doi.org/10.3390/biology15131001
  27. FASEB J. 2026 Jul 31. 40(14): e72132
    Mechanical Loading Induces Distinct and Shared Responses in Endothelial and Muscle Cells and Reveals Exercise-Like Molecular Profiles.
    Sakari Mäntyselkä, Erik Niemi, Laura Ylä-Outinen, Kalle Kolari, Liina Uusitalo-Kylmälä, Alfredo Ortega-Alonso, Roosa-Maria Liimatainen, Vasco Fachada, Perttu Permi, Elina Kalenius, Juha J Hulmi, Riikka Kivelä.
      Skeletal muscles and blood vessels are continuously exposed to mechanical forces, particularly during exercise. We subjected human endothelial and skeletal muscle cells to cyclic mechanical stretch to mimic exercise and investigated acute molecular responses. Mechanical loading elicited both shared and cell type-specific alterations in transcriptomic and metabolomic profiles, several of which mirrored changes observed in vivo following exercise. Both cell types released acetate in response to mechanical loading, at least partly via reactive oxygen species-dependent mechanism. Interestingly, transcriptomic changes occurred in opposite directions in endothelial and muscle cells. For example, genes associated with the electron transport chain were repressed in endothelial cells but upregulated in skeletal muscle cells. In endothelial cells, mechanical loading promoted a transcriptomic shift indicative of increased barrier integrity and attenuated proliferation. Metabolic changes were more pronounced in endothelial cells, which exhibited increased serine biosynthesis from glucose, as demonstrated by 13C-(U)-glucose tracing. Targeting phosphoglycerate dehydrogenase (PHGDH), a key enzyme in the serine synthesis pathway, underscored the role of serine biosynthesis in endothelial cell anabolism. These findings suggest that mechanical loading recapitulates several exercise-induced effects in endothelial and muscle cells, and highlights a potential link between mechanical stimuli, serine synthesis, and endothelial cell quiescence.
    Keywords:  PHGDH; acetate; mechanical force; metabolomics; serine; transcriptomics
    DOI:  https://doi.org/10.1096/fj.202503958RRR
  28. Mol Med. 2026 Jul 15.
    ACL injury reprograms quadriceps myonuclear epigenetic and transcriptional signatures in mice.
    Nicholas T Thomas, Camille R Brightwell, Thomas Carter, Alexander R Keeble, Sara Gonzalez-Velez, Christine M Latham, Allison M Owen, Yuan Wen, Kevin A Murach, Christopher S Fry.
       BACKGROUND: ACL injury is a debilitating sport-related injury that induces prolonged deficits in muscle size and strength. Using a time-course of in vivo fluorescent metabolic labeling of nascent RNA in an ACL injury mouse model, we identified upregulated myonuclear transcriptional output early following the injury.
    METHODS: To define altered myonuclear transcription, we bred HSArtTA/rtTA:TetO-H2B-GFP mice to allow for stable in vivo fluorescent labeling and sorting of resident (non-satellite cell-derived) myonuclei 3-days post ACL transection surgery. We performed myonucleus-specific RNA sequencing (RNAseq) and reduced representation bisulfite sequencing (RRBS) to capture altered myonuclear transcriptional and epigenetic signatures following ACL injury.
    RESULTS: Integration of these datasets revealed transcriptional reprogramming of quadriceps myonuclei following ACL injury toward upregulation of fibrosis related genes and downregulation of metabolism related genes. When integrating bulk tissue RRBS with bulk tissue RNAseq, we demonstrate a similar, but more robust pattern of transcriptional reprogramming, suggesting the altered epigenetic landscape following ACL injury extends beyond myonuclei.
    CONCLUSIONS: Our results support a model of epigenetically-encoded muscle maladaptation following orthopedic injury, with implications for understanding a "muscle memory" of persistent dysfunction.
    Keywords:  Extracellular matrix; Injury; Muscle memory; Myonuclei; Skeletal muscle
    DOI:  https://doi.org/10.1186/s10020-026-01568-4
  29. Sci Rep. 2026 Jul 17.
    Intermittent time-restricted feeding improves physical performance and modulates mitochondrial morphology in a muscle fiber type dependent manner in middle-aged mice.
    Fernanda Briones-Manríquez, Gonzalo Almarza, Bastián Ramos, María José Silva-Urbina, Luciana Pesce, Valentina Jeria, Javiera Aranda, Amanda Grau-Grass, Francisco Díaz-Castro, Juan Carlos Bórquez, Luis A Videla, Carla Basualto-Alarcón, Franco Tacchi, Marianny Portal-Rodriguez, Rodrigo Troncoso, Claudio Cabello-Verrugio, Andrea Del Campo.
      Sarcopenia, defined as the age-related decline in skeletal muscle mass and function, markedly reduces physical performance, threatens functional independence, and diminishes quality of life in older adults. Although the clinical manifestations of sarcopenia typically emerge later in life, underlying molecular alterations, particularly within the mitochondrial network, occur well before symptom onset. Growing evidence indicates that dietary interventions, including caloric restriction as well as changes in meal timing, composition, and overall intake, play a critical role in attenuating age-associated pathologies. Time-restricted feeding (TRF) is a dietary regimen in which all caloric intake is confined to a defined daily time window and has emerged as a feasible and widely adopted variant of caloric restriction. This study investigates the effects of inactive phase TRF on skeletal muscle health in a middle-aged murine model, with a particular focus on its potential to delay or attenuate the decrease of physical performance only by modifying daily feeding schedules. Our findings demonstrate that inactive phase TRF allows to dissect the impact of mistimed nutrient intake and confers beneficial effects on skeletal muscle, including improved muscle strength and maintenance of basal glycemia during early aging. These effects were accompanied by a tendency to increase succinate dehydrogenase (SDH) expression and significantly reduced lipid droplet accumulation. These effects correlate with muscle type-specific adaptations of the mitochondrial network and sarcoplasmic reticulum-mitochondria interaction in response to TRF. Collectively, these findings support the potential of inactive phase TRF as an easy-to-follow therapeutic intervention during middle age to maintain physical performance in early aging.
    Keywords:  Middle-age; Mitochondrial dynamics; Sarcopenia; Time-restricted feeding
    DOI:  https://doi.org/10.1038/s41598-026-60902-2
  30. Biochem Biophys Res Commun. 2026 Jul 15. pii: S0006-291X(26)01057-0. [Epub ahead of print]830 154293
    UFC1 maintains ACSL3 abundance through UFMylation-associated mechanisms to modulate lipid metabolism in skeletal muscle myoblasts.
    Mali Guo, Junjie Xu, Haiyan Xie, Ping Li, Wei Zhang, Fanghui Chen, Yafei Cai.
      Ordered proliferation of skeletal muscle myoblasts is essential for muscle development and repair and requires coordinated metabolic remodeling. Acyl-CoA synthetase long-chain family member 3 (ACSL3) activates long-chain fatty acids and thereby supports lipid metabolic flux, but the post-translational mechanisms regulating ACSL3 in myoblasts remain incompletely defined. UFMylation is a ubiquitin-like post-translational modification mediated by a cascade that includes the E2-conjugating enzyme UFC1. Here, we investigated whether UFC1 regulates ACSL3 abundance and lipid metabolism in C2C12 myoblasts and primary mouse skeletal muscle myoblasts. UFC1 knockout or knockdown reduced ACSL3 protein abundance, decreased myoblast proliferation, and lowered cellular neutral and polar lipid signals. Transcriptomic gene set enrichment analysis further indicated suppression of pathways related to unsaturated fatty acid biosynthesis and fatty acid metabolism after UFC1 loss. Co-immunoprecipitation showed an association between UFC1 and ACSL3, and endogenous immunoprecipitation detected a UFC1-dependent UFM1 signal on ACSL3. Cycloheximide chase assays indicated accelerated ACSL3 degradation in UFC1-deficient cells, whereas the proteasome inhibitor MG132 partially restored ACSL3 protein abundance. Overexpression of ACSL3 alleviated lipid metabolic defects and partially rescued proliferation in UFC1-deficient myoblasts. These findings suggest that UFC1 contributes to ACSL3 protein abundance, probably through UFMylation-associated suppression of proteasomal degradation, thereby supporting lipid homeostasis and proliferation in skeletal muscle myoblasts.
    Keywords:  ACSL3; Lipid metabolism; Skeletal muscle myoblasts; UFC1; UFMylation
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154293
  31. Function (Oxf). 2026 Jul 17.
    Constitutive mTORC1 Activation in Skeletal Muscle Increases Inflammation but is not Sufficient to Impair Glucose Tolerance.
    Erik D Marchant, Hanna Kalenta, Sean P Kilroe, Jacquelyn May, Wenjun Z Martini, Korri S Weldon, Zhao Lai, Blake B Rasmussen.
      Aberrant mechanistic target of rapamycin complex 1 (mTORC1) signaling in skeletal muscle has been implicated in aging and insulin resistance, however, it is not known whether chronic mTORC1 activation directly causes glucose intolerance. We tested the hypothesis that constitutive mTORC1 activation in mouse skeletal muscle impairs glucose homeostasis. Six-month-old female and male mice with tamoxifen-inducible, muscle-specific knockout of Depdc5, a key component of the GATOR1 complex and negative regulator of mTORC1, were fed normal chow or western diet (WD; 45% fat, 17% sucrose) for 12 weeks. Depdc5 knockout (KO) increased mTORC1 signaling and altered autophagy markers. WD increased body and fat mass and impaired glucose tolerance independent of genotype. KO had minimal effects on fasting glucose, insulin, HOMA-IR, HbA1c, or oral glucose tolerance, although female KO mice showed a modest increase in WD-induced weight gain and fasting glucose. Mitochondrial respiration and content were unchanged by KO or WD. KO increased mitochondrial Hâ''Oâ'' production capacity but did not drive clear signs of oxidative stress. Transcriptomic analysis revealed robust KO-driven upregulation of genes related to cell division and immune pathways. Consistent with this, KO increased TNF-α and IL-6 protein expression and shifted macrophage polarization toward an M2-like phenotype without altering total macrophage content. Collectively, these findings indicate that chronic activation of mTORC1 in skeletal muscle promotes inflammatory remodeling but is insufficient to impair systemic glucose homeostasis, even under dietary stress.
    DOI:  https://doi.org/10.1152/function.039.2026
  32. Front Cell Dev Biol. 2026 ;14 1854844
    Urolithin A enhances mitochondrial biogenesis-related markers and maximal respiratory capacity during C2C12 differentiation.
    Ronald Vargas-Foitzick, Diego Irribarra-Tapia, Mayalen Valero-Breton, Elisa Balboa.
       Introduction: Skeletal muscle differentiation in the C2C12 myoblast model requires extensive mitochondrial remodeling to meet rising bioenergetic demands through coordinated changes in biogenesis, dynamics, and respiratory adaptation. Urolithin A (UA), a gut microbiota-derived metabolite of ellagitannins, improves mitochondrial health, but its role in late-stage myogenic differentiation remains unclear.
    Methods: C2C12 myotubes were treated with UA (2 μM) for 72 h during late-stage differentiation (days 3-6). Mitochondrial signaling, respiratory capacity, myogenic morphology, and ultrastructure were assessed by Western blot, high-resolution respirometry, hematoxylin-eosin staining, and transmission electron microscopy.
    Results: UA was non-cytotoxic and increased AMPKα phosphorylation and PGC-1α expression, whereas TOM20, MFN2, and OPA1 were unchanged. Mitophagy/autophagy-related markers (p-ULK1, p62, BNIP3L/NIX, LC3-II/I) were not altered, indicating no detectable changes in steady-state autophagy under the conditions tested. UA selectively increased OXPHOS Complex I and II abundance and enhanced maximal uncoupled respiration, and was associated with increased myotube diameter and myogenic marker abundance. No overt ultrastructural differences were observed by electron microscopy.
    Discussion: These findings suggest that UA promotes mitochondrial functional adaptation during myogenic differentiation, with accompanying changes in myogenic phenotype, without clear evidence of altered steady-state mitophagy/autophagy markers or mitochondrial morphology.
    Keywords:  C2C12 myotubes; maximal respiration; myogenic differentiation; oxphos; urolithin A
    DOI:  https://doi.org/10.3389/fcell.2026.1854844
  33. Aging Cell. 2026 Jul;25(7): e70629
    Epigenetic Aging of Critical Illness Survivors Assessed by the Muscle-Specific "Clock" and Its Relationship With Reduced Long-Term Muscle Strength.
    Ceren Uzun Ayar, Inge Derese, Greet Van den Berghe, Ilse Vanhorebeek.
      Critically ill patients requiring treatment in the intensive care unit (ICU) suffer from muscle weakness that persists for years. As compared with healthy subjects, skeletal muscle of patients biopsied five years post-ICU revealed an abnormal transcriptome partially associated with poor muscle strength. We now hypothesized that skeletal muscle of long-term ICU survivors is "epigenetically aged", as determined by a muscle-specific epigenetic clock, and that such accelerated epigenetic aging contributes to their long-term muscle weakness. Muscle DNA-methylation data from former ICU patients at 5-year follow-up (N = 118) and healthy controls (N = 160), aged 18-89 years, were analyzed by the MEATv2 epigenetic clock. First, epigenetic age (DNAmAge), epigenetic minus chronological age (AADiff) and epigenetic age acceleration (AAResid) were compared between 97 former patients and 97 controls, propensity score-matched for age and sex. Next, the impact of any muscle-specific epigenetic aging of ICU survivors was investigated, via multivariable models, as a potential contributor to the altered transcriptome and reduced muscle strength. Former ICU patients showed a significantly higher muscle DNAmAge, AADiff, and AAResid than matched controls. In adjusted models, higher muscle DNAmAge, AADiff, or AAResid did not substantially contribute to differentially expressed muscle RNAs in former patients as compared with controls and was not associated with the poor long-term muscle strength. In conclusion, five years after ICU discharge, former patients showed accelerated epigenetic aging in skeletal muscle. However, the muscle-specific epigenetic clock did not capture molecular changes that are associated with long-term muscle weakness, which highlights the need for other muscle-specific biological predictors of age-related physical impairment. Trail Registration: ClinicalTrials.gov: NCT00512122.
    Keywords:  DNA methylation; RNA expression; critical illness; epigenetic aging; epigenetic clock; intensive care unit; muscle weakness; post‐intensive care syndrome
    DOI:  https://doi.org/10.1111/acel.70629
  34. Mol Cell Biol. 2026 Jul 14. 1-16
    PUF60 is a Critical Regulator of PKM Splicing During Myogenesis.
    So Masaki, Takayuki Nojima, Takako Oshiro-Ideue, Asami Suenaga, Akihide Takeuchi, Isao Kii, Kenji Suzuki, Satoshi Tanaka, Masatoshi Hagiwara, Naoyuki Kataoka.
      Pyruvate kinase M (PKM) catalyzes the conversion of phosphoenolpyruvate to pyruvate in glycolysis and exists as two splice isoforms, PKM1 and PKM2, generated from alternative splicing of mutually exclusive exons 9 or 10, respectively. The expression balance between PKM1 and PKM2 is tightly regulated in a cell-type-specific manner. PKM1 is predominantly expressed in tissues such as skeletal muscle, heart, and brain, whereas PKM2 is prevalent in most other tissues and various cancer cells. Despite its importance, the trans-acting factors promoting exon 9 selection in a tissue-specific context remain largely unknown. Here, using a multi-color splicing reporter system for cell-based cDNA screening, we identified PUF60 as a novel trans-acting factor that promotes PKM1-type splicing. We also demonstrated that PUF60 induction and the resulting splicing switch are essential for myotube formation during C2C12 differentiation. This study establishes PUF60 as a critical regulator of muscle-specific splicing and provides new insights into the fundamental mechanisms governing skeletal muscle differentiation.
    Keywords:  Alternative splicing; PKM; PUF60; muscle differentiation
    DOI:  https://doi.org/10.1080/10985549.2026.2699151
  35. Exp Lung Res. 2026 ;52(1): 143-153
    The role of ABHD2 in cigarette smoke-induced skeletal muscle atrophy in chronic obstructive pulmonary disease mice: The mechanism of ABHD2 in skeletal muscle atrophy.
    Qingyan Lin, Jun Liu, Han Xie, Honghao Chen, Shoude Jin.
      Background: Chronic obstructive pulmonary disease (COPD) is a major and increasing global health problem that results in progressive airway obstruction. Cigarette smoke (CS) exposure, a major cause for COPD, induces mitochondrial damage, which has been implicated in sarcopenia pathogenesis. The current study sought to examine the involvement of ABHD2 in the mechanisms of development of COPD-related sarcopenia. Methods: The involvement of ABHD2 was examined using in vivo CS-exposure model using ABHD2-KO mice. In CSE-induced COPD mouse models, ROS production and inflammation were measured using fluorescent probes and Western blot analysis. Results: Increased ROS was responsible for myotube atrophy by activating Muscle Ring Finger 1 and inhibiting Myod. ABHD2-KO mice with prolonged CS exposure showed enhanced muscle atrophy. Conclusion: These results indicated that ABHD2 played a key protective role in COPD-related skeletal muscle atrophy through a three-dimensional interactive network coordinating angiogenesis, oxidative stress defense, and inflammatory microenvironment regulation.
    Keywords:  ABHD2; COPD; ROS; skeletal muscle atrophy
    DOI:  https://doi.org/10.1080/01902148.2026.2694260
  36. Anim Sci J. 2026 Jan-Dec;97(1):97(1): e70221
    Peroxisome Proliferator-Activated Receptor Delta Regulates Myogenic Differentiation via Lipid Droplet-Associated Metabolic Remodeling and p38 MAPK Signaling.
    Rumana Mahzabin, Md Rezwanul Habib, Yukako Tokutake, Shinichi Yonekura.
      Skeletal muscle development and metabolic regulation are critical for livestock productivity and meat quality. This study investigated the role of peroxisome proliferator-activated receptor delta (PPARδ) in myogenic differentiation and lipid droplet (LD) formation, focusing in particular on p38 mitogen-activated protein kinase (MAPK) signaling. C2C12 myoblasts were induced to differentiate and treated with the PPARδ agonist GW501516 or antagonist GSK3787. Myogenic differentiation was then assessed via myosin heavy chain immunostaining and calculation of the fusion index and myotube area. LD formation was evaluated by BODIPY staining and analysis of Plin2 expression. Activation of p38 MAPK was analyzed via Western blotting, and its role was examined using the inhibitor SB203580. Activation of PPARδ significantly enhanced myogenic differentiation, whereas its inhibition suppressed this process. PPARδ activation also promoted LD formation and upregulated Plin2 expression during early differentiation. In addition, GW501516 increased p38 MAPK phosphorylation. Inhibition of p38 MAPK markedly attenuated both LD formation and myogenic differentiation induced by PPARδ activation. These findings demonstrate that PPARδ promotes myogenic differentiation through coordinated lipid metabolic remodeling and p38 MAPK signaling, highlighting an association between metabolic regulation and muscle differentiation. This pathway may represent a potential target for improving muscle development and meat quality in livestock.
    Keywords:  lipid metabolism; myogenic differentiation; p38 mitogen‐activated protein kinase signaling; peroxisome proliferator‐activated receptor delta; skeletal muscle
    DOI:  https://doi.org/10.1111/asj.70221
  37. Metabolism. 2026 Jul 17. pii: S0026-0495(26)00209-X. [Epub ahead of print]183 156696
    TRIM72 alleviates skeletal muscle atrophy by modulating mt-dsRNA/RIG-I signaling.
    Liwei Liao, Ziwen Zheng, Weidong Xu, Junwei Guo, Simin Yao, Xinyue Huang, Zilin Wang, Chang Li, Jiaye Li, Qin Zhang, Yiding Bian, Kai Wang, Jinrui Miao, Ruixia Li, Han Wang, Xiaoming Zhou, Mingming Deng, Gang Hou.
      Skeletal muscle atrophy is characterized by diminished muscle mass and function, which can arise from aging, nerve damage, and disease-related secondary atrophy. A central unresolved question is how these diverse stressors trigger common downstream mechanisms to cause sustained muscle deterioration. Here, we confirmed the role of cytosolic double-stranded RNA (dsRNA) in muscle atrophy across multiple murine models (aging, denervation and dexamethasone). Accumulated dsRNA released from damaged mitochondria aberrantly activated the innate immune sensor RIG-I signaling, triggering inflammation and muscle wasting. Moreover, adoptive transfer of mitochondrial dsRNA (mt-dsRNA) into healthy myotubes was sufficient to recapitulate the atrophic phenotype and activate RIG-I signaling. Furthermore, E3 ligase TRIM72 was identified as muscle-specific regulator of RIG-I signaling. TRIM72 attenuates the mt-dsRNA/RIG-I axis through two mechanisms. One is ubiquitinating RIG-I via interaction with its CARD domain to trigger degradation, the other is preserving mitochondria to prevent dsRNA leakage. Consequently, TRIM72 deficiency exacerbated atrophy while supplementation with recombinant TRIM72 (rhT72) improved muscle conditions and suppressed RIG-I signaling in vivo. In a clinic cohort, plasma TRIM72 level declined with muscle atrophy across multiple pathologies and rose with muscle recovery. Overall, our findings revealed mt-dsRNA/RIG-I axis as a key pathogenic pathway in muscle atrophy and identified TRIM72 as a key regulator and potential therapeutic agent.
    Keywords:  Mitochondrial double-stranded RNA (mt-dsRNA); RIG-I; Skeletal muscle atrophy; Tripartite motif containing 72 (TRIM72)
    DOI:  https://doi.org/10.1016/j.metabol.2026.156696
  38. Cancer Metastasis Rev. 2026 Jul 17. pii: 47. [Epub ahead of print]45(3):
    Understanding cachexia and muscle dysfunction in the context of metastatic breast cancer.
    Alastair A E Saunders, Robin L Anderson, Paul Gregorevic.
      Cancer cachexia significantly impacts the quality of life of cancer patients, predicting therapy response and survival. Cachexia prevalence and severity increases over the course of disease progression, affecting up to 80% of patients with metastatic cancer. Despite this, cachexia is relatively understudied in the context of metastatic breast cancer, despite it affecting a significant proportion of patients with this common cancer. In this review we highlight the relative prevalence of cachexia in breast cancer, with 25% of all patients and up to half of those with metastatic disease impacted. Given the metastatic distribution pattern of breast cancer (e.g. high rates of bone metastases), we reviewed the unique systemic and local muscle cues leading to cachexia in this context and have reviewed areas for further investigation. Furthermore, anti-cancer therapies also contribute to cachexia progression. Recently, novel mouse models for study of cachexia in breast cancer have been developed. These models can further the field's understanding of cachexia in metastatic cancer patients and aid in the development of anti-cachectic agents. However, it is important that these models accurately recapitulate human disease. In this review we provide an appraisal of the relative utility of the currently available models. Overall, this review highlights that understanding cachexia in the context of breast cancer and metastasis may uncover novel mechanisms to target this condition, thereby improving the quality of life and survival prospects of metastatic cancer patients.
    Keywords:  Breast cancer; Cachexia; Metastasis; Models; Muscle; Sarcopenia
    DOI:  https://doi.org/10.1007/s10555-026-10358-7
  39. Animal Model Exp Med. 2026 Jul 17.
    Effectiveness of intermittent hypoxia on muscle recovery in rats: A systematic review.
    Sebastian Philippe Hansen Quiblier, María García-Arrabé, Diego Domínguez-Balmaseda, Guillermo García-Pérez-de-Sevilla.
      The objective of this review was to synthesize evidence from animal models on the effects of intermittent hypobaric hypoxia (IHH), cold exposure, and their combinations, with or without exercise, on skeletal muscle recovery after fatigue or injury. The review systematically examined controlled animal studies evaluating hypoxia- or cold-based interventions for muscle recovery. The data sources PubMed, SPORTDiscus, Web of Science, and Scopus were searched up to July 2025 following PRISMA guidelines (PROSPERO CRD420251013029). Studies deemed eligible for inclusion were interventional animal studies assessing IHH, cold exposure, or combined protocols and reporting functional, physiological, or mechanistic outcomes. Risk of bias was evaluated using RoB 2. Five studies met inclusion criteria. IHH protocols simulated ~4000-4500 m for several hours per day, while cold exposure used ~4°C; some studies added low-intensity treadmill exercise. IHH alone enhanced muscle regeneration, reduced fibrosis, and improved contractile force compared with passive recovery. Combined with aerobic exercise, IHH maintained oxidative capacity and increased PGC-1α and VEGF expression, supporting angiogenesis. Cold exposure elevated mitochondrial complex expression but increased oxidative stress, whereas IHH improved redox balance. IHH plus light exercise also raised circulating CD34+ and endothelial progenitor cells, suggesting improved repair capacity. Overall risk of bias was rated as "some concerns," mainly due to limited reporting of randomization. Our conclusion is that IHH shows potential to enhance muscle regeneration and redox balance in animal models. Its application in athletic recovery is promising, but standardized protocols and human trials are required before translation.
    Keywords:  animal model; exercise; hypoxia; intermittent hypobaric hypoxia; oxidative stress; recovery
    DOI:  https://doi.org/10.1002/ame2.70248
  40. Sci Rep. 2026 Jul 16.
    Use of organ transplant solution to preserve skeletal muscle for cellular and spatial transcriptomic analyses.
    Pediatric Cell Atlas of SkeletalMuscle consortium
      Single-cell and spatial transcriptomic technologies have revolutionized human cell and tissue research. Success of these methods critically depends on the preservation of RNA integrity, cellular viability, and structure of the explanted tissues-features that are impacted by tissue storage conditions, and pose challenges in research settings, where tissues are often collected in the operating room and transported to distant laboratories. In this study, we evaluated the effectiveness of a clinically approved organ transplant solution (TS) for preserving skeletal muscle under refrigerated conditions. Using murine and human skeletal muscle tissues we found that compared to buffered saline, TS consistently maintained higher RNA quality, preserved tissue morphology, and supported successful primary cell culture and spatial transcriptomic analysis of murine and human muscle samples obtained from different surgical collection sites. These findings establish a foundation for the use of a standardized protocol for live muscle tissue preservation for reliable downstream transcriptomic analyses for multicenter research efforts.
    DOI:  https://doi.org/10.1038/s41598-026-58534-7
  41. Exp Gerontol. 2026 Jul 14. pii: S0531-5565(26)00217-2. [Epub ahead of print]222 113238
    Human umbilical cord-derived mesenchymal stem cells ameliorate muscle dysfunction and metabolic dysregulation in the CuZnSOD null mouse model of sarcopenia.
    Gilbert Aaron Lee, Li-Wen Tseng, Yu-Wei Chang, Hen-Yu Liu, Hong-You Lin, Hui-Ling Chen, Bo-Syong Pan, Duen-Pang Kuo, Sung-Hui Tseng.
      Age-related sarcopenia is a progressive skeletal muscle disorder driven by oxidative stress and metabolic dysregulation. Cu/Zn superoxide dismutase-deficient (Sod1-/-) mice recapitulate key features of oxidative stress-induced muscle degeneration and provide a robust preclinical model for mechanistic and therapeutic studies. Here, we investigated whether systemic administration of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) could modulate muscle function and metabolic homeostasis under both pathological and physiological conditions. In Sod1-/- mice, UC-MSC treatment significantly improved motor coordination and grip endurance, restored gastrocnemius myofiber number, markedly reduced mitochondrial reactive oxygen species production and catalase expression levels in skeletal muscle, and restored muscle ATP content. UC-MSCs also restored circulating insulin-like growth factor-1 (IGF-1) levels. Untargeted lipidomic profiling revealed profound depletion of lipid species in Sod1-/- muscle, particularly omega-3 fatty acids, which was selectively rescued by UC-MSC therapy, including restoration of α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid, without substantial recovery of disrupted polar metabolic pathways such as aminoacyl-tRNA biosynthesis. In contrast, UC-MSC administration in wild-type mice induced a distinct metabolic remodeling characterized by reduced n-3 and n-6 fatty acid-associated lipid species and concomitant enrichment of fructose-related glycolytic intermediates, indicating a shift toward carbohydrate-based energy utilization in metabolically intact muscle. Together, these findings demonstrate that UC-MSCs function as context-dependent metabolic modulators, alleviating oxidative stress-induced sarcopenia through attenuation of oxidative stress, restoration of systemic IGF-1, and selective reprogramming of lipid metabolism, while dynamically adjusting energy metabolism in physiological skeletal muscle.
    Keywords:  Metabolism; Sacropenia; Umbilical cord-derived mesenchymal stem cells
    DOI:  https://doi.org/10.1016/j.exger.2026.113238
  42. Neurol Neuroimmunol Neuroinflamm. 2026 Sep;13(5): e200525
    Muscle Regeneration Failure May Lead to Clinical Features of Myopathy in Anti-IgLON5 Disease.
    Yvette S Crijnen, Verena Endmayr, Suzanne C Franken, Nadine A M E Van Der Beek, Maartje Louter, Thomas Ströbel, Ellen Gelpi, Inga Koneczny, Ryuichi Shigemoto, Jan Lewerenz, Birgit Högl, Julia V Wanschitz, Ulrich He Hofstadt-Van Oy, Robin W Van Steenhoven, Mariska M P Nagtzaam, Jeroen Kerstens, Juliette Brenner, Anna E M Bastiaansen, Robert M Verdijk, Thierry P P Van Den Bosch, Marco Schreurs, Sharon Veenbergen, Marcel M Verbeek, Dave L Roelen, Mar Guasp, Peter A E Sillevis Smitt, Lidia Sabater, Juna M de Vries, Romana Höftberger, Maarten J Titulaer.
       BACKGROUND AND OBJECTIVES: Anti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease is a novel and potentially treatable entity. Therefore, it is important to recognize all clinical symptoms and diagnostic clues. We specifically investigated neuromuscular signs and symptoms and muscle biopsy pathology, providing a link between IgLON5 and clinical features of myopathy.
    METHODS: All patients diagnosed with anti-IgLON5 disease in the Netherlands between 2016 and 2023 were included. Serum and CSF samples were tested with immunohistochemistry on rat brain and in-house cell-based assay using live cells. Biopsies of the vastus lateralis muscle were performed in patients with neuromuscular signs and symptoms and analyzed in Vienna together with 3 biopsies of non-Dutch patients sent to Vienna for second opinion.
    RESULTS: Twenty patients with anti-IgLON5 disease were included (10 male, 50%). The median age at onset was 61.5 years (range 45-85), and the median time from onset to diagnosis was 30 months (range 3-280). Neuromuscular symptoms were present in over half of the patients (11/20), including proximal limb weakness (n = 11), axial weakness (n = 1), muscle atrophy (n = 6), and fasciculations (n = 5). All 12 muscle biopsies (9 from the Dutch cohort, 3 external) showed mild myopathic alterations, 2 additionally presented target fibers and fiber type grouping (compatible with neurogenic myopathy), and 3 patients showed immune cell infiltration. We found a strong upregulation of IgLON5 expression in muscle fibers in all patients and also in different muscle disease controls, while immunoreactivity in healthy control muscle was faint/absent.
    DISCUSSION: Our data support that IgLON5 might play a role in muscle regeneration, which might result in proximal myopathy as a prominent clinical feature in anti-IgLON5 disease. This finding broadens the clinical phenotype of anti-IgLON5 disease and can be an important clue for earlier diagnosis and start of immunotherapy.
    DOI:  https://doi.org/10.1212/NXI.0000000000200525
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