bims-moremu 2026-07-26 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–07–26
twenty-six papers selected by
Anna Vainshtein, Craft Science Inc.

The local-systemic axis of the skeletal muscle secretome.
Oxytocin as a regulator of skeletal muscle plasticity and metabolic function.
The Divergent Effects of Nicotinamide Riboside and High-Intensity Exercise Training on Skeletal Muscle Epigenetic Aging.
Fast and slow skeletal muscle: Different overall activation levels and kinetics of myosin motors underlie muscle type-specific contractile properties.
Cellular signaling within aged skeletal muscle reveals a dysregulated stress-induced remodeling response following volumetric muscle loss in female mice.
GDF5 modulation of MuSC pool as a potential therapeutic benefit for DMD.
Skeletal muscle adaptation to microgravity: how altered mechanical cues drive catabolic signaling.
Single-cell resolution of skeletal muscle aging: Current paradigms and perspectives.
ER stress-dependent Ddit4/REDD1 induction contributes to translational suppression during cisplatin-induced skeletal muscle atrophy.
Selective Small-Molecule AdipoR1 Agonist 3-Hydroxy Pterocarpan Salt (CDRI-1709S) Ameliorates Skeletal Muscle Atrophy.
Multi-organ transcriptome profiling in an isogenic cachexia-inducing xenograft model to dissect host responses across heart, liver, kidney, and muscle.
Exercise training attenuates high-fat diet-induced skeletal muscle atrophy by inhibiting Drp1-mediated cuproptosis in male mice.
Microdystrophins partially rescue deficits of duchenne muscular dystrophy iPSC-cardiomyocytes.
Context-dependent regulation of IL-6 in exercise and colorectal cancer cachexia.
SUMOylation modulates glucocorticoid-induced muscle toxicity in cell and mouse models.
Enhanced HGF with increased receptor affinity and nitration-dysfunction resistance through interaction with lipoic acid trisulfide.
Comparing aerobic and resistance training in estrogen deficiency: bone and muscle adaptations.
Do Exercise-Induced Extracellular Vesicles Carry Cognitive Benefits to the Brain?
The Injection of miR-1/133 Antagonist Notably Accelerated the Healing Process of Exercise-Induced Skeletal Muscle Injury.
Miro1-mediated mitochondrial transfer boosts stem cell therapy for muscle atrophy via restoring mitochondrial homeostasis.
Cigarette Smoke-Exposed Alveolar Epithelial Cell-Derived Exosomes Exacerbate Skeletal Muscle Dysfunction Through HDAC2 Signalling.
Mechanism of actin thin filament pointed-end elongation by leiomodin.
Capillary endothelial cell heterogeneity in skeletal muscle of female and male mice.
Effects of six weeks of hypoxia and hypoxic SIT on oxidative stress and myokine responses in skeletal muscle of high-fat-fed ApoE-/- mice.
GIP Acutely Blunts Insulin- and GLP-1-Induced Muscle Microvascular Perfusion.
Circadian Clock Interaction with HIF1α Mediates Oxygenic Metabolism and Anaerobic Glycolysis in Skeletal Muscle.

Trends Endocrinol Metab. 2026 Jul 24. pii: S1043-2760(26)00172-4. [Epub ahead of print]

The local-systemic axis of the skeletal muscle secretome.

Sean Y Ng, Christoph Handschin.

  Exercise stimulates the release of bioactive factors, termed exerkines, that contribute to local and systemic adaptation. Circulating exerkines are often interpreted as direct readouts of muscle secretion, overlooking regulatory processes within tissues that shape their production, transformation, and release. Using skeletal muscle and endurance exercise as a model system, we define a local-systemic secretome axis shaped by spatial organization, stimulus-specific programs, temporal dynamics, extracellular processing, and paracrine circuitry. By integrating evidence from recent transcriptomics, proteomics, interstitial fluid, and extracellular vesicle studies, we outline how these processes govern signal propagation from muscle to circulation and inform the interpretation of circulating exerkines as biomarkers and therapeutic targets.

Keywords:  exercise adaptation; exerkine; paracrine signaling; secretome; skeletal muscle

DOI:  https://doi.org/10.1016/j.tem.2026.07.001
Front Endocrinol (Lausanne). 2026 ;17 1863901

Oxytocin as a regulator of skeletal muscle plasticity and metabolic function.

Joao da Cruz-Filho, Danilo Lustrino.

  Although skeletal muscle has historically been considered a non-target tissue of oxytocin (OXT), accumulating evidence demonstrates that this neuropeptide influences myogenesis, regeneration, and protein metabolism, thereby modulating muscle plasticity through neuroendocrine signaling axes. Among physiological and pathological contexts, variations in circulating OXT are associated with changes in muscle mass. For example, anabolic steroid exposure promotes muscle hypertrophy alongside increased OXT levels, whereas aging and diabetes are characterized by muscle loss and reduced OXT. Mechanistically, OXT activates its receptor (OXTR), a G protein-coupled receptor, engaging Gαq signaling, intracellular calcium mobilization, and downstream pathways such as Akt-FoxO, thus linking central neuropeptide signaling to peripheral metabolic regulation. This crosstalk inhibits proteolysis while stimulating protein synthesis. Consistent with these findings, preclinical and clinical studies support a protective role of OXT in muscle mass regulation. However, key aspects of OXT biology in skeletal muscle remain poorly understood, including the regulation of its synthesis, degradation, and secretion under physiological and pathological conditions, which may influence its local and systemic actions. As a myokine, OXT may integrate local muscle signaling with systemic neuroendocrine actions, operating through autocrine, paracrine and endocrine mechanisms, although the relative contributions remain unresolved. In this context, emerging evidence on OXT signaling in skeletal muscle, particularly its role in regulating muscle plasticity, provides a conceptual framework that is explored throughout this review.

Keywords:  muscle mass; oxytocin; oxytocin receptor; proteolysis; skeletal muscle

DOI:  https://doi.org/10.3389/fendo.2026.1863901
Aging Cell. 2026 Aug;25(8): e70638

The Divergent Effects of Nicotinamide Riboside and High-Intensity Exercise Training on Skeletal Muscle Epigenetic Aging.

Aino Heikkinen, Liina Uusitalo-Kylmälä, Ida Blom, Jørn Wulff Helge, Linn Gillberg, Robert Seaborne, Steen Larsen, Macsue Jacques, Robin Grolaux, Sari Aaltonen, Jaakko Kaprio, Birgitta W van der Kolk, Sini Heinonen, Nir Eynon, Kirsi H Pietiläinen, Riikka Kivelä, Eija Pirinen, Miina Ollikainen.

  Aging is accompanied by a decline in physiological function and increased vulnerability to disease, with mitochondrial dysfunction and epigenetic alterations recognized as key hallmarks. Nicotinamide riboside (NR), a vitamin B3 precursor to NAD+, and high-intensity interval training (HIIT) have both been proposed to ameliorate aging-related mitochondrial decline, but their effects on skeletal muscle epigenetic aging are not fully elucidated. Here, we assessed the impact of 5-month NR supplementation and 4-6 weeks HIIT on epigenetic age acceleration (EAA, via seven epigenetic clocks) in human skeletal muscle across three independent studies. NR supplementation was associated with reduced muscle EAA, particularly when measured with the PCHannum, MEAT, and DunedinPACE clocks, while HIIT produced opposite effects in some clocks, notably increasing pace of aging by DunedinPACE. Correlation analyses revealed that changes in skeletal muscle mitochondrial content correlated with changes in MEAT-derived EAA after NR and 6 weeks of HIIT. Together, these findings indicate that skeletal muscle epigenetic aging can be modulated by NR and HIIT interventions but in opposing directions, highlighting a potential link between mitochondrial abundance and epigenetic clocks. Further studies are warranted to clarify how NR and exercise regulate epigenetic aging. These results offer new insights into development of strategies for promoting epigenetic outcomes and healthy aging.

Keywords:  epigenetic aging; high‐intensity interval training; mitochondria; nicotinamide riboside; skeletal muscle; twins

DOI:  https://doi.org/10.1111/acel.70638
J Physiol. 2026 Jul 23.

Fast and slow skeletal muscle: Different overall activation levels and kinetics of myosin motors underlie muscle type-specific contractile properties.

Daniel Z Kruse, Jon Herskind, Angelos Angelidis.



Keywords:  muscle type‐specific myosin activation; skeletal muscle myosin; thick filament activation; time‐resolved X‐ray diffraction

DOI:  https://doi.org/10.1113/JP291637
Physiol Rep. 2026 Jul;14(14): e71022

Cellular signaling within aged skeletal muscle reveals a dysregulated stress-induced remodeling response following volumetric muscle loss in female mice.

Krista M Habing, Tyler J Sagendorf, Cynthia A Alcazar-Daleo, James A Sanford, Damon Leach, Joshua C Vanderpool, Chelsea M Hutchinson-Bunch, Marina Gritsenko, Gina M Many, Karina H Nakayama.

  Severe muscle trauma disrupts endogenous repair mechanisms and produces chronic functional deficits that are poorly defined in aging. We investigated inflammatory, molecular, and physiological responses to volumetric muscle loss in young adult and aged female mice. Cytokine profiling revealed elevated baseline inflammation in aged mice and a blunted early injury response; for example, IL-6 increased 4.4-fold in young versus 1.8-fold in aged mice at day 3 post-injury. By day 28, histological analyses revealed comparable reductions in muscle size and increased fibrosis across ages. Despite similar structural pathology, age-dependent differences emerged in functional and molecular adaptations. Both groups exhibited persistent force deficits; however, aged muscles showed significantly altered relaxation kinetics (p < 0.001), suggesting dysregulated excitation-contraction coupling. Aged mice also demonstrated altered post-injury limb loading patterns. Global proteomics identified age-associated enrichment of complement and antigen-processing pathways and signatures of metabolic dysfunction (p < 0.05). Phosphoproteomic analysis revealed reduced basal kinase activity in aged muscle but exaggerated injury-induced phosphorylation of Mapk1-associated sites indicating a dysregulated stress response. Together, these findings indicate that aging muscles operate within a heightened inflammatory and perturbed kinase-signaling environment that may impair coordinated regeneration and functional recovery following traumatic injury.

Keywords:  aging; inflammation; muscle regeneration; phosphoproteomics; stress response; volumetric muscle loss

DOI:  https://doi.org/10.14814/phy2.71022
Mol Ther Nucleic Acids. 2026 Sep 08. 37(3): 103005

GDF5 modulation of MuSC pool as a potential therapeutic benefit for DMD.

Christel Gentil, Aly Bourguiba, Amélie Vergnol, Bruno Cadot, Zoheir Guesmia, Lucile Saillard, Pierre Meunier, Bénédicte Hoareau-Coudert, Mégane Lemaitre, Sestina Falcone, Lorenzo Giordani, France Pietri-Rouxel.

  Duchenne muscular dystrophy (DMD) is a fatal disease caused by dystrophin deficiency, leading to degeneration of the entire musculature. To improve muscle pathophysiology and gene therapy for DMD, we investigated the potential of growth differentiation factor 5 (GDF5) in the DMD mdx mouse model. We showed that the overexpression of GDF5 in the muscle improved its histology, reduced inflammation, modulated regeneration, and induced the appearance of de novo fibers. We demonstrated that muscle satellite cells (MuSCs) are targeted by GDF5, which enhanced their proliferation and slowed down their myogenic commitment and finally their fusion. When combined with AAV-mediated microdystrophin gene therapy, the leading therapeutic strategy, GDF5 further increased the proportion of small microdystrophin-positive fibers compared to gene therapy alone. These findings highlight GDF5 as a promising modulator of DMD pathology and provide the first evidence of an additive effect of the combination of GDF5-based intervention and AAV-microdystrophin treatment.

Keywords:  AAV-microdystrophin; Duchenne muscular dystrophy; GDF5; MT: delivery strategies; gene therapy; muscle satellite cells MuSC; skeletal muscle

DOI:  https://doi.org/10.1016/j.omtn.2026.103005
EMBO Rep. 2026 Jul 21.

Skeletal muscle adaptation to microgravity: how altered mechanical cues drive catabolic signaling.

Sandhya Singh, Samrat Chakraborty, Shenhav Shemer.

Exposure to microgravity induces rapid and profound skeletal muscle atrophy, yet the mechanisms by which reduced mechanical loading is sensed and translated into coordinated cellular and tissue-level responses remain incompletely understood. Accumulating evidence indicates that muscle adaptation to microgravity arises from disruption of mechanosensing pathways that regulate membrane signaling, cytoskeletal organization, and extracellular matrix (ECM) structure. Here, we integrate findings from spaceflight, bed rest, immobilization, and in vitro models to examine how reduced mechanical loading alters muscle-intrinsic signaling and tissue architecture. We discuss early suppression of anabolic pathways, activation of proteolytic systems, and remodeling of membrane-associated signaling hubs, including ECM composition, stiffness, and integrin-mediated adhesion. We further highlight how coupling between the ECM, cytoskeleton, and the nucleus enables mechanical cues to shape transcriptional programs and metabolic control during unloading. Understanding how skeletal muscle adapts to altered mechanical forces will facilitate the development of therapies for atrophy in spaceflight and terrestrial conditions of disuse, including bed rest, aging, and immobilization.

DOI: https://doi.org/10.1038/s44319-026-00879-1
Ageing Res Rev. 2026 Jul 23. pii: S1568-1637(26)00264-3. [Epub ahead of print]121 103272

Single-cell resolution of skeletal muscle aging: Current paradigms and perspectives.

Yanteng Wang, Yichen Yang, Wenwei Guan, Wan Yu, Na Li, Difei Wang.

  Skeletal muscle aging is a complex biological process that involves coordinated changes in multiple cell types. Recent breakthroughs in single-cell sequencing technology have provided new perspectives regarding this process. Here, we systematically summarize current progress in single-cell technology with respect to skeletal muscle aging. We focused on specific molecular characteristics and interaction networks of muscle fiber, satellite and immune cells during aging. Aging skeletal muscles develop cellular heterogeneity such as a decline in stem cell function, formation of a chronic inflammatory microenvironment, and remodeling the extracellular matrix. We integrated multi-omics data to identify potential intervention targets and explored precise anti-aging strategies using single-cell data. Although this field has significantly progressed, persistent challenges include technical methods, data integration, and clinical translation. Future studies are needed to optimize single-cell analysis techniques, deepen understanding of cell interaction mechanisms, and promote the translation of related findings into clinical applications. These will provide vital references for understanding the molecular basis of muscle aging and developing new intervention methods.

Keywords:  Anti-aging; Cellular heterogeneity; Single-cell sequencing; Skeletal muscle

DOI:  https://doi.org/10.1016/j.arr.2026.103272
Chem Biol Interact. 2026 Jul 18. pii: S0009-2797(26)00368-6. [Epub ahead of print]437 112260

ER stress-dependent Ddit4/REDD1 induction contributes to translational suppression during cisplatin-induced skeletal muscle atrophy.

Hayato Nanri, Hiroyasu Sakai, Kaisei Umeyama, Takayuki Ogiwara, Shinki Soga, Yuya Chigusa, Shiori Yonamine, Risako Kon, Nobutomo Ikarashi, Yoshihiko Chiba, Kumiko Ogawa.

  Cisplatin is a widely used chemotherapeutic agent whose clinical utility is limited by various adverse effects. Although skeletal muscle loss during chemotherapy is often attributed to cachexia or generalized wasting, accumulating evidence indicates that cisplatin directly induces skeletal muscle atrophy. However, the underlying cellular stress responses and signaling pathways remain unclear. In this study, we investigated the involvement of endoplasmic reticulum (ER) stress and translational regulation in cisplatin-induced skeletal muscle atrophy, focusing on DNA damage-inducible transcript 4/Regulated in development and DNA damage response-1 (Ddit4/REDD1), a stress-responsive inhibitor of mammalian target of rapamycin complex 1 (mTORC1). Using a mouse model and differentiated C2C12 myotubes, we examined ER stress signaling, protein synthesis, and mTORC1 activity following cisplatin treatment, and evaluated the effects of tauroursodeoxycholic acid (TUDCA), an ER stress-suppressing chemical chaperone. Cisplatin induced skeletal muscle atrophy accompanied by ER stress activation and suppression of protein synthesis in mice. TUDCA significantly attenuated muscle mass and strength loss without affecting body weight reduction. Cisplatin upregulated ER stress-responsive genes and decreased phosphorylation of p70 S6 kinase, whereas these changes were suppressed by TUDCA. Pharmacological ER stress induction increased Ddit4/REDD1 expression, and PERK inhibition reduced cisplatin-induced Ddit4/REDD1 upregulation in C2C12 myotubes. Furthermore, Ddit4/REDD1 knockdown partially restored protein synthesis and mTORC1 signaling. These findings indicate that cisplatin induces skeletal muscle atrophy via ER stress-associated translational suppression, at least partly through Ddit4/REDD1-mediated inhibition of mTORC1.

Keywords:  Cisplatin; Ddit4/REDD1; ER stress; Muscle atrophy; mTORC1

DOI:  https://doi.org/10.1016/j.cbi.2026.112260
J Cachexia Sarcopenia Muscle. 2026 Aug;17(4): e70328

Selective Small-Molecule AdipoR1 Agonist 3-Hydroxy Pterocarpan Salt (CDRI-1709S) Ameliorates Skeletal Muscle Atrophy.

Md Rameez Moin, Shyamal Pal, Shubhrajyoti Das, Pallavi Awasthi, Anushka Talukdar, Akhilesh Kumar, Shruti Suhas Varode, Nikhil Nikolas, Shamima Khatoon, Madhav Nilkanth Mugale, Rajdeep Guha, Sabyasachi Sanyal, Atul Goel.

   BACKGROUND: Skeletal muscle atrophy is a frequent comorbidity of metabolic disorders and chronic diseases, and despite its high prevalence, no pharmacological therapy is available, representing a major unmet clinical need. Adiponectin and its receptors are key regulators of skeletal muscle metabolism, mitochondrial function and myogenesis, yet clinical translation has been hindered by the lack of receptor-selective agonists with favourable pharmacological and safety profiles. Here, we report the identification and characterization of CDRI-1709S, the first small-molecule AdipoR1-selective agonist and evaluate its myogenic and anti-atrophy efficacy.
METHODS: A PGC-1α luciferase reporter-based screen in AdipoR1/AdipoR2-transfected, AdipoR-low HEK293T cells identified CDRI-1709S as an AdipoR1 agonist. Adiponectin-associated signalling events were evaluated by immunoblotting in AdipoR1/2-overexpressing HEK293T cells and AdipoR-abundant C2C12 myotubes, with receptor specificity confirmed using RNA interference. Myogenic potential was assessed by morphometric analysis and immune detection of myogenic factors. Fibre-type composition and metabolic capacity were evaluated using immunoblotting and extracellular flux analysis. Anti-atrophy effects were examined in vitro using various assault-induced models of myotube atrophy, and in vivo using rat models of dexamethasone (Dex) and sciatic nerve denervation-induced muscle atrophy.
RESULTS: CDRI-1709S selectively activated AdipoR1 with high potency (EC50: 414.7pM) and, at a pharmacologically relevant concentration (100 nM), induced rapid adiponectin-associated signalling, including phosphorylation of AMPK, AKT and p38-MAPK, along with upregulation of its downstream skeletal muscle metabolic targets PGC-1α, GLUT4 and UCP3 in an AdipoR1-dependent manner (p < 0.05). CDRI-1709S promoted C2C12 myoblast differentiation into mature myotubes, accompanied by increased expression of MyoD and myogenin (p < 0.05). Treated myotubes were protected against cytokine-, Dex- and nutrient-deprivation-induced atrophy through suppression of atrogenes Atrogin-1 and MuRF-1 (p < 0.01), restoration of myogenic markers (p < 0.05) and prevention of Dex-induced fibre-type switching toward glycolytic MyHC-IIB, with concomitant induction of slow (MyHC-I) and fast (MyHC-IIA) oxidative fibres (p < 0.05). CDRI-1709S also reversed Dex-mediated impairments in oxidative and glycolytic capacity (p < 0.05). Oral administration of CDRI-1709S (10 mg/kg/day) in Dex- and denervation-induced rat models restored atrogene expression, myogenic markers, local adiponectin signalling and myofibrillar architecture to normalcy (p < 0.05 to p < 0.0001). CDRI-1709S prevented Dex-induced enrichment of glycolytic fibres and preserved oxidative fibre composition (p < 0.05). The structural/molecular improvements translated into significant functional enhancements, including toe-spread reflex in denervated limbs (p < 0.05) and increased grip strength (p < 0.0001) plus prolonged wire-hang duration (p < 0.01) in Dex-treated animals.
CONCLUSION: CDRI-1709S is the first AdipoR1-selective small-molecule agonist that induced myogenesis and robustly ameliorated skeletal muscle atrophy, establishing the proof-of-concept for AdipoR1-targeting as a promising therapeutic strategy for sarcopenia and skeletal muscle atrophy.

Keywords:  AdipoR1 agonist; adiponectin; muscle fibre‐type; muscle function improvement; skeletal muscle atrophy

DOI:  https://doi.org/10.1002/jcsm.70328
Hum Cell. 2026 Jul 19. pii: 112. [Epub ahead of print]39(8):

Multi-organ transcriptome profiling in an isogenic cachexia-inducing xenograft model to dissect host responses across heart, liver, kidney, and muscle.

Julia Osaki, Yomogi Shiota, Ikumi Fujita, Kazuyoshi Yanagihara, Tadashi Kondo.

  Cancer cachexia is a debilitating systemic syndrome that affects a substantial proportion of patients with advanced malignancy and is associated with impaired treatment tolerance, reduced quality of life, and increased mortality. While skeletal muscle wasting is a defining clinical feature, cachexia involves coordinated dysfunction across multiple organs, yet it remains unclear whether cachexia imposes a unified, body-wide transcriptional program or primarily induces organ-specific responses. Here, we leveraged an isogenic xenograft model derived from human duodenal neuroendocrine carcinoma in which the cachexia-inducing subline AkuNEC was established through in vivo serial passaging from the parental, largely non-cachexia-inducing line TCC-NECT-2. We performed bulk RNA sequencing of skeletal muscle, liver, kidney, and heart from cachectic AkuNEC-bearing mice, non-cachectic TCC-NECT-2-bearing mice, and uninoculated controls. Differential expression analyses identified organ-dependent sets of transcripts associated with cachexia. However, unsupervised analyses of global expression patterns consistently showed that tissue identity dominated transcriptome structure and samples did not segregate by cachexia status. In addition, comparisons of tumor-bearing vs uninoculated controls revealed broadly similar transcriptional shifts for AkuNEC and TCC-NECT-2 within each organ. Together, these data indicate that cachexia-associated transcriptional changes are present but remain modest relative to dominant tissue-specific programs at the whole-transcriptome level. The AkuNEC/TCC-NECT-2 system provides a controlled platform for future studies incorporating cell-type-resolved, spatial, and multi-omic approaches to delineate the mechanisms linking tumor evolution to multi-organ remodeling in cancer cachexia.

Keywords:  AkuNEC; Cancer cachexia; Duodenal neuroendocrine carcinoma; Heart; Kidney; Liver; Multi-organ dysfunction; RNA-seq; Skeletal muscle; TCC–NECT-2; Transcriptomics; Xenograft

DOI:  https://doi.org/10.1007/s13577-026-01412-1
Cell Signal. 2026 Jul 23. pii: S0898-6568(26)00412-2. [Epub ahead of print] 112755

Exercise training attenuates high-fat diet-induced skeletal muscle atrophy by inhibiting Drp1-mediated cuproptosis in male mice.

Min Hu, Yiwen Yuan, Zhenxian An, Jiahao Wang, Xuebin Li, Xuejing Liu, Wenhao Zhang, Zujie Xu, Xiaoqin Zhao.

   OBJECTIVE: The present study investigated the role of Drp1 in cuproptosis and its underlying mechanisms, while examining the effects of aerobic exercise on high-fat diet-induced skeletal muscle atrophy. These findings may provide a theoretical basis for exercise interventions and targeted therapies for obesity-associated skeletal muscle atrophy.
METHODS: Five-week-old male C57BL/6 J mice (n = 10 per group) were randomly assigned to a normal diet (ND) or high-fat diet (HFD) and subsequently subjected to aerobic exercise or Mdivi-1 intervention for 8 weeks. Body composition, skeletal muscle mass, grip strength, and endurance capacity were evaluated. Muscle morphology, mitochondrial function, oxidative stress, and copper homeostasis were assessed using H&E staining, JC-1 staining, DHE staining, biochemical assays, and copper measurements. Muscle atrophy proteins, Drp1, and cuproptosis markers were assessed at protein and mRNA levels by Western blotting, immunofluorescence, and RT-qPCR. Differences among multiple groups were analyzed using two-way ANOVA, whereas differences between two groups were analyzed using Student's unpaired t-test.
RESULTS: HFD induced skeletal muscle atrophy, as evidenced by reduced muscle mass, grip strength, and endurance capacity. This was accompanied by mitochondrial dysfunction, oxidative stress, and increased expression of Drp1 and cuproptosis-related markers. Aerobic exercise significantly ameliorated these pathological changes. Similar protective effects were observed following pharmacological inhibition of Drp1 with Mdivi-1.
CONCLUSIONS: Aerobic exercise alleviates HFD-induced skeletal muscle atrophy by suppressing Drp1 expression, thereby reducing copper accumulation and cuproptosis in skeletal muscle.

Keywords:  Aerobic exercise; Cuproptosis; Drp1; High-fat diet; Skeletal muscle atrophy

DOI:  https://doi.org/10.1016/j.cellsig.2026.112755
Mol Ther Adv. 2026 Sep 10. 34(3): 201801

Microdystrophins partially rescue deficits of duchenne muscular dystrophy iPSC-cardiomyocytes.

Abiageal R Keegan, Adriana Fernanda G S Gonzalez, Rongruo Zhang, Hung Doan, Sofía I Torres-Bigio, Fiona Lau, Kaulen N Ly, Elaine C Lai, Leahlyn C Mamuyac, Sriram Bhimaraju, Abhishree Mishra, Michelle K Polen, Daniel S Ortiz, Jay H Lam, Asuka Eguchi.

  Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by the lack of dystrophin. Dilated cardiomyopathy is the leading cause of death in DMD patients. Smaller variants of dystrophin, called microdystrophins, amenable to packaging into adeno-associated virus (AAV), have been shown to be effective in improving skeletal muscle function in animal models. However, the functional benefit of these microdystrophins in the DMD heart remains unclear. To determine the efficacy of microdystrophin gene therapy, we compared three microdystrophin variants in DMD cardiomyocytes (CMs) differentiated from human induced pluripotent stem cells (iPSCs). We used three DMD lines of different genetic backgrounds and benchmarked against controls expressing full-length dystrophin. We also tested a dystrophin variant, minidystrophin, which is larger than the microdystrophins. Our results show that microdystrophins partially rescue disease phenotypes; however, the results are variable among genetic backgrounds. Global transcriptional profiling revealed that gene therapy altered the disease signatures of DMD iPSC-CMs. Minidystrophin significantly improved cell viability of DMD CMs in two of three lines of different genetic backgrounds. Minidystrophin also reduced arrhythmic events in one genetic background. Our findings suggest that the delivery of larger dystrophin variants may be more beneficial to delaying the onset of cardiac complications.

Keywords:  Duchenne muscular dystrophy; cardiomyopathy; dystrophin; gene therapy; iPSC; induced pluripotent stem cell; microdystrophin

DOI:  https://doi.org/10.1016/j.omta.2026.201801
Front Oncol. 2026 ;16 1792184

Context-dependent regulation of IL-6 in exercise and colorectal cancer cachexia.

Jingwen Xiong, Sihan Liu, Jie Xu, Jinghan Zhang, Yundong Peng, Yibei Xia, Jinghua Qian.

  Colorectal cancer (CRC) is a common malignancy of the digestive system and remains a major cause of cancer-related morbidity and mortality worldwide. Its development and progression are influenced by genetic susceptibility, lifestyle factors, metabolic dysregulation, and chronic inflammatory states. Cancer cachexia is a multifactorial wasting syndrome characterized by weight loss, skeletal muscle atrophy, metabolic disturbances, and functional decline, which substantially impairs quality of life and survival outcomes in patients with CRC. In this context, interleukin-6 (IL-6) has emerged as a context-dependent regulatory mediator linking inflammation, metabolism, tumor biology, and skeletal muscle wasting. The biological effects of IL-6 are shaped by signaling mode, cellular source, concentration, temporal dynamics, and the broader tumor-host environment. This review discusses the regulatory roles of IL-6 in CRC and CRC-related cachexia, with particular attention to exercise-associated IL-6 responses. Rather than viewing exercise-induced IL-6 as inherently beneficial or antitumor, we emphasize that IL-6 is one component of a broader exercise-responsive network involving metabolic adaptation, immune regulation, skeletal muscle function, and systemic inflammatory remodeling. We also summarize current evidence regarding how exercise modality and intensity may influence IL-6 dynamics, while distinguishing mechanistic and preclinical findings from limited and heterogeneous human data. Overall, IL-6 dynamics may provide a hypothesis-generating framework for understanding exercise responses in CRC-related cachexia, but current evidence is insufficient to support IL-6-guided individualized exercise prescription or therapeutic decision-making in clinical practice.

Keywords:  IL-6; cachexia; colorectal cancer (CRC); exercise oncology; exercise therapy

DOI:  https://doi.org/10.3389/fonc.2026.1792184
Sci Rep. 2026 Jul 21.

SUMOylation modulates glucocorticoid-induced muscle toxicity in cell and mouse models.

Ahyoung Lee, Yoonhee Jeong, Hayeong Kwon, Myeongsu Kim, Seulmin Kim, Philyoung Lee, Changwon Kho.

  Prolonged glucocorticoid (GC) exposure is a clinically relevant cause of skeletal muscle atrophy through activation of glucocorticoid receptor (GR)-dependent catabolic transcriptional programs, including those mediated by Krüppel-like factor 15 (KLF15). However, the post-translational regulatory mechanisms that modulate the magnitude of GC-driven catabolic signaling in skeletal muscle remain incompletely understood. In this study, we investigated the role of SUMOylation as a stress-responsive post-translational regulatory mechanism in GC-induced muscle toxicity. Pharmacological modulation of SUMOylation was examined using the SUMOylation activator N106 in differentiated C2C12 myotubes and in a DEX-treated mouse model, both subjected to dexamethasone (DEX) treatment. Morphological, transcriptional, and functional parameters were assessed in vitro and in vivo, and the requirement for SUMO conjugation was interrogated using the SUMO E1 inhibitor TAK981. DEX exposure was associated with reduced SUMO-conjugated protein levels and induced a robust GR-KLF15-dependent catabolic transcriptional response in skeletal muscle cells and tissues. Enhancement of SUMOylation by N106 attenuated DEX-induced reductions in myotube diameter and muscle fiber cross-sectional area and suppressed the induction of muscle atrogenes (Fbxo32, Trim63) and metabolic enzymes (Pdk4, Bcat2). In vivo, N106 mitigated DEX-associated impairments in muscle function, including grip strength and treadmill endurance. In contrast, pharmacological inhibition of SUMOylation by TAK981 enhanced GC-induced catabolic gene expression, supporting an important role for SUMO conjugation in regulating skeletal muscle stress responses. Collectively, these findings identify SUMOylation as a post-translational regulatory layer that constrains GR-mediated catabolic transcription under GC stress. Chemical modulation of the SUMOylation pathway influences the severity of GC-induced muscle atrophy, highlighting SUMOylation as an important determinant of skeletal muscle susceptibility to GC-induced toxicity.

Keywords:  SUMOylation; dexamethasone, post-translational modification; glucocorticoids; muscle atrophy

DOI:  https://doi.org/10.1038/s41598-026-60353-9
Sci Rep. 2026 Jul 24. pii: 22053. [Epub ahead of print]16(1):

Enhanced HGF with increased receptor affinity and nitration-dysfunction resistance through interaction with lipoic acid trisulfide.

Kahona Zushi, Miyumi Seki, Ryota Mizuochi, Kazuki Shitamitsu, Alaa Elgaabari, Sakiho Tanaka, Junri Miyamoto, Kaoru Mizoguchi, Reina Fujimaru, Jiaxi Han, Takashi Nakashima, Shoko Sawano, Wataru Mizunoya, Takahiro Maeno, Issei Yokoyama, Takahiro Suzuki, Judy E Anderson, Ryuichi Tatsumi.

  Myogenic stem cell activator HGF (hepatocyte growth factor) undergoes nitration of tyrosine residues (Y198, Y250) predominantly on fast-twitch fibers to lose its binding affinity to the signaling receptor c-met, in response to peroxynitrite (ONOO-) generation during aging. Here we show that HGF adopts an enhanced form with dynamically increased receptor-binding affinity and nitration-dysfunction resistance through interaction with lipoic acid trisulfide (LASSS) under physiological conditions. When evaluated after exposure to LASSS at a 1:8000 molar ratio to HGF and subsequent ultra-filtration to wash-out un-reacted free LASSS, c-met binding affinity increased more than two-fold over the original non-nitrated HGF. The same LASSS treatment also conferred nitration resistance with a greater effect for Y198 than Y250, indicating a novel mechanism independent of an anti-oxidative function of LASSS. Neither glutathione trisulfide (GSSSG, a potent anti-oxidant) nor lipoic acid enhanced c-met binding or nitration resistance, and thus served as controls. Importantly, pre-administration of LASSS to mice prevented the disuse-induced HGF nitration observed in a tail-suspension model for muscle atrophy, while GSSSG did not. The findings encourage the idea that LASSS may react with HGF to enhance its receptor-binding affinity and nitration resistance, which are known to strongly drive myogenic stem cell dynamics and homeostasis. Application of this model could potentially lead to pioneering strategies to counteract or treat age-related muscle atrophy and impaired regeneration with fibrosis and fat infiltration (including sarcopenia and frailty).

Keywords:  C-Met binding affinity; Hepatocyte growth factor (HGF); Lipoic acid trisulfide (LASSS); Mouse and rat; Muscle atrophy; Peroxynitrite; Resident myogenic stem satellite cell; Tyrosine nitration

DOI:  https://doi.org/10.1038/s41598-026-60835-w
Climacteric. 2026 Jul 23. 1-9

Comparing aerobic and resistance training in estrogen deficiency: bone and muscle adaptations.

Pedro Gustavo Machado, Juliana Cristina Dos Reis Canaan, Luciana Botelho Ribeiro, José Victor Mauricio de Jesus, Heloisa Oliveira Dos Santos, Natália Oliveria Bertolini, Ivam Moreira de Oliveira Júnior, Wilson Vicente Souza Pereira, Eric Francelino Andrade, Luciano José Pereira.

   OBJECTIVE: The reduction in bone mass and deterioration of bone microarchitecture are hallmark consequences of estrogen deficiency during menopause, increasing susceptibility to osteopenia and osteoporosis. Physical exercise is recognized as an effective non-pharmacological strategy; however, the comparative effects of different exercise modalities on bone remodeling and muscle-bone crosstalk remain unclear. This study investigated the effects of aerobic and resistance training on femoral bone metabolism and skeletal muscle adaptations in ovariectomized (OVX) mice.
METHOD: Sixty-four female C57BL/6J mice underwent ovariectomy or sham surgery and were allocated to sedentary, aerobic (treadmill running) or resistance (ladder climbing) training protocols for 8 weeks. Bone histological and histochemical analyses, skeletal muscle morphology and gene expression in bone and muscle tissues were evaluated.
RESULTS: Both training modalities significantly increased the osteoblast number and reduced the osteoclast density in OVX animals compared with sedentary controls (p < 0.05), accompanied by a reduction in the RANKL/osteoprotegerin (OPG) ratio (p < 0.001). Resistance training induced more pronounced effects, including higher osteocyte density (p < 0.01), greater RUNX2 expression (p < 0.001) and stronger suppression of osteoclastogenesis. In parallel, resistance training significantly increased the muscle fiber cross-sectional area (p < 0.05) and upregulated IGF-1 (p < 0.01) and FNDC5 expression (p < 0.05).
CONCLUSION: These findings demonstrate that exercise mitigates estrogen deficiency-induced bone deterioration, with resistance training exerting superior effects on bone remodeling and musculoskeletal integration.

Keywords:  Estrogen deficiency; bone remodeling; muscle–bone crosstalk; resistance training

DOI:  https://doi.org/10.1080/13697137.2026.2694475
Traffic. 2026 Sep;27(3): e70046

Do Exercise-Induced Extracellular Vesicles Carry Cognitive Benefits to the Brain?

Oliver K Fuller, Thierry Galli.

Exercise-induced muscle-brain communication mediated by extracellular vesicles. Physical exercise stimulates skeletal muscle to release extracellular vesicles (EVs) into the circulation. These vesicles may reach the brain and transfer bioactive cargo such as miRNA, thereby supporting neuronal function and brain homeostasis and potentially protecting against the onset or progression of neurodegenerative diseases.

DOI: https://doi.org/10.1111/tra.70046
Physiol Res. 2026 Jul 22. 75(3): 569-584

The Injection of miR-1/133 Antagonist Notably Accelerated the Healing Process of Exercise-Induced Skeletal Muscle Injury.

X Liu, M Yuan, N Zhang, J Xing.

Exercise-induced muscle damage (EIMD) significantly impacts daily work and life. The rapid promotion of repair for EIMD is worthy of attention. This study aimed to investigate the effect and mechanism of microRNAs in treating EIMD. By establishing an acute skeletal muscle injury model, we determined the key time point for skeletal muscle injury repair and the time-specific changes in MRTF-A/Pax7/SRF and muscle regeneration factors during the repair process. MicroRNAs antagonists were injected to verify the targeting relationship between miR-1/133a and MRTF-A/Pax7/SRF. A single bout of acute eccentric exercise caused significant damage to the morphological ultrastructure of rat gastrocnemius muscles, with the most severe injuries occurring 72 h after exercise. At this particular time point, it was identified as crucial for damage repair. Both miR-1-3p and miR-133a-3p collectively targeted and suppressed the protein translation of MRTF-A, Pax7, and SRF. Furthermore, both miR-1-3p and miR-133a-3p antagonists targeted the MRTF-A/Pax7 axis as well as the MRTF-A/SRF axis. MiR-1-3p antagonists primarily promote muscle proliferation and differentiation, while miR-133a-3p antagonists mainly promote differentiation while inhibiting atrophy. Combined injection effectively promote both muscle proliferation and differentiation while inhibiting atrophy, thereby facilitating damage repair in skeletal muscle fiber structure. Key words Exercise " Muscle damage " Skeletal muscle regeneration " MRTF-A " Pax7 " SRF.
Stem Cell Res Ther. 2026 Jul 20.

Miro1-mediated mitochondrial transfer boosts stem cell therapy for muscle atrophy via restoring mitochondrial homeostasis.

Fangling Zhao, Jingxin Fu, Linli Gao, Mengting Zhou, Yuhui Xia, Zexian Zhao, MengNa Yang, Jiahui He, Wei Zhu, Mengxiong Pan, Kaiming Liu.

  Mitochondrial dysfunction underlies the major defect in muscle atrophy (characterized by the loss of skeletal muscle mass and function). Mesenchymal stem cells (MSCs), which can mediate mitochondrial transfer (MT) via tunneling nanotubes (TNTs), have been shown to exert therapeutic effects, yet the underlying mechanism remains unclear. Mitochondrial Rho GTPase 1 (Miro1) is crucial for regulating mitochondrial homeostasis; in this study, we aimed to investigate the roles of Miro1 and Milton in MSC-based therapy for muscle atrophy. Dexamethasone (DEX)-induced C2C12 cells and chronically aged mice were used as in vitro cellular and in vivo muscle atrophy models, respectively. In vitro experiments demonstrated that overexpression of Milton alone failed to enhance MT in DEX-induced C2C12 cells. Although Milton could promote the formation of TNTs, it was unable to drive mitochondrial movement along microtubules in the absence of Miro1.In contrast, Miro1 knockdown (MSCmiro1Lo) significantly reduced MT in vivo, while Miro1 overexpression (MSCmiro1Hi) improved mitochondrial morphology, increased muscle fiber count and cross-sectional area, upregulated the expression of type I/III collagen, and downregulated the expression of Atrogin1 and MURF1. Additionally, Miro1 overexpression ameliorated functional outcomes such as grip strength, running distance, and physical activity, and elevated the levels of proteins related to mitochondrial fusion, mitophagy, and biogenesis in damaged muscle cells. These findings indicate that Miro1 is a critical driver of MT, and Miro1-enhanced MT confers substantial in vivo therapeutic benefits. This study provides robust evidence supporting Miro1 as a potential target for the treatment of muscle atrophy-related disorders.

Keywords:  Miro1; Mitochondrial homeostasis; Mitochondrial transfer; Muscle atrophy; Stem cells

DOI:  https://doi.org/10.1186/s13287-026-05191-2
J Cachexia Sarcopenia Muscle. 2026 Aug;17(4): e70349

Cigarette Smoke-Exposed Alveolar Epithelial Cell-Derived Exosomes Exacerbate Skeletal Muscle Dysfunction Through HDAC2 Signalling.

Chao Li, MingZhi Ou, Gang Jiang, GuiXian Zheng, YongLiang Jiang.

   BACKGROUND: Skeletal muscle dysfunction (SMD) is a common extrapulmonary complication of chronic obstructive pulmonary disease (COPD). Histone deacetylase 2 (HDAC2) is closely involved in the suppression of inflammatory transcription and is progressively reduced during COPD progression. Exosomes mediate intercellular communication by transferring bioactive cargos, including proteins. This study aimed to elucidate the molecular mechanism by which alveolar epithelial cell-derived exosomes regulate HDAC2 and contribute to COPD-related SMD.
METHODS: Exosome inhibitor GW4869 was used to assess the role of exosomes in skeletal muscle injury induced by chronic cigarette smoke (CS) exposure. Exosomes isolated from the bronchoalveolar lavage fluid (BALF) of CS-exposed mice and from cigarette smoke extract (CSE)-exposed mouse alveolar epithelial (MLE12) cells were applied to recipient mice and/or mouse myoblast (C2C12) cells to evaluate muscle phenotypes, myogenic differentiation and cellular senescence. Rescue experiments using HDAC2 overexpression or HDAC activator ITSA1 treatment, together with proteomics and protein interaction assays, were performed to elucidate the underlying molecular mechanisms.
RESULTS: GW4869 treatment ameliorated CS-induced muscle dysfunction in mice, as evidenced by increased grip strength (222.4 ± 15.91 g vs. 159.2 ± 11.65 g, p < 0.001) and muscle fibre cross-sectional area (404.0 ± 5.15 μm2 vs. 172.0 ± 5.39 μm2, p < 0.001), along with decreased muscle atrophy and senescence markers. In vitro, exosomes derived from 8% CSE-exposed MLE12 cells (Exo-CSE) impaired myogenic differentiation, decreased myotube diameter (10.50 ± 0.74 μm vs. 29.27 ± 0.48 μm, p < 0.001) and increased the number of senescent cells (206.7 ± 5.13 vs. 9.33 ± 1.53, p < 0.001). Exo-CSE significantly reduced HDAC2 expression in C2C12 cells (0.18 ± 0.03 vs. 0.53 ± 0.04, p < 0.001), whereas HDAC2 overexpression or ITSA1 treatment rescued impaired myogenic differentiation and cellular senescence caused by Exo-CSE. Proteomic analysis identified proline/arginine-rich end leucine-rich protein (PRELP) as a key exosomal cargo, and exosomes derived from PRELP-silenced CSE-exposed MLE12 cells markedly restored HDAC2 expression in recipient C2C12 cells (0.42 ± 0.02 vs. 0.18 ± 0.03, p < 0.001). Mechanistically, PRELP disrupted the stabilizing interaction between heat shock protein family A member 5 (HSPA5) and HDAC2, accelerating HDAC2 degradation, likely through the ubiquitin-proteasome pathway. In vivo, the combination of PRELP knockdown and the HDAC activator ITSA1 synergistically alleviated CS-induced muscle atrophy and senescence.
CONCLUSIONS: In COPD, CS-exposed alveolar epithelial cells release PRELP-enriched exosomes that promote SMD by disrupting HSPA5-mediated HDAC2 stabilization and accelerating HDAC2 degradation. Targeting the PRELP-HDAC2 axis may represent a potential therapeutic strategy for COPD-related SMD.

Keywords:  COPD; HDAC2; crosstalk; exosomes; skeletal muscle dysfunction

DOI:  https://doi.org/10.1002/jcsm.70349
Nat Commun. 2026 07 20. pii: 6675. [Epub ahead of print]17(1):

Mechanism of actin thin filament pointed-end elongation by leiomodin.

Shayna B Brotzman, Nicholas J Palmer, Malgorzata Boczkowska, Roberto Dominguez.

In non-muscle cells, actin filaments exhibit variable lengths and rapid turnover, with subunits adding primarily at the barbed end. The situation is strikingly different in striated muscle sarcomeres, where despite rapid turnover, actin thin filaments exhibit uniform length and exchange subunits primarily at the pointed end. This filament length uniformity is tightly regulated by several proteins, including the molecular ruler nebulin in skeletal muscle and the barbed- and pointed-end capping proteins CapZ and tropomodulin (Tmod) in both skeletal and cardiac muscles. Recent studies in cells and animal models have identified leiomodin-2 (Lmod2) as an additional regulator proposed to promote pointed-end elongation to maintain thin filament length. This activity would make leiomodin the only known eukaryotic factor to drive pointed-end elongation, yet its molecular mechanism remains unresolved. Here, we present a series of cryo-electron microscopy structures that support a stepwise elongation mechanism in which two Lmod2 molecules alternate at the pointed end while recruiting actin monomers. These findings establish the molecular basis of pointed-end elongation in muscle sarcomeres and provide a framework for understanding mutations in Lmod2 that cause dilated cardiomyopathy.

DOI: https://doi.org/10.1038/s41467-026-74810-6
Physiol Rep. 2026 Jul;14(14): e71025

Capillary endothelial cell heterogeneity in skeletal muscle of female and male mice.

Mackenzie E Charter, Coral L Murrant.

  In skeletal muscle, capillaries have been shown to be critical to active hyperemia by sensing skeletal muscle activity and directing blood flow to contracting muscle fibers. There is evidence to suggest that capillary endothelial cell (EC) characteristics may change along the length of a capillary. This longitudinal heterogeneity may have implications on capillary function with respect to their role in active hyperemia. We sought to determine whether EC characteristics differed along the length of a capillary. We perfused 5 female and 6 male CD-1 mice with fluorescently labeled Wheat Germ Agglutinin (WGA) and GS-IB4 Isolectin (ISO) which bind to different carbohydrate sites on the EC glycocalyx. We imaged capillaries along their length in fresh whole mounts of the gluteus maximus, diaphragm, soleus, extensor digitorum longus, and cremaster muscles. We observed that WGA labeled capillaries across their entire length while ISO only stained the arteriolar end of capillaries. These findings were observed in all muscles in females and males. These data show that the constituents of the capillary EC glycocalyx are not consistent across the length of a capillary. This capillary heterogeneity may have important implications for the microvascular response during active hyperaemia and blood flow control during muscle contraction.

Keywords:  capillary; endothelial cell; glycocalyx; microvasculature; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.71025
Eur J Appl Physiol. 2026 Jul 21.

Effects of six weeks of hypoxia and hypoxic SIT on oxidative stress and myokine responses in skeletal muscle of high-fat-fed ApoE-/- mice.

Yangwenjie Wang, Jessica Lavier, Linjia Wang, Weicheng Hua, Hao Wei, Changle Zhao, Maxime Pellegrin, Grégoire P Millet, Ying Zhang.

  Atherosclerosis-induced oxidative stress drives skeletal muscle myopathy in peripheral artery disease, yet the combined effects of hypoxia and hypoxia sprint interval training (SIT) remain unclear. The present study was designed to evaluate how a six-week regimen of hypoxia exposure and SIT influences redox balance and myokine production in the skeletal muscle of high-fat diet (HFD) (21% fat, 1.5% (w/w) cholesterol; 43% (w/w) sucrose-free carbohydrate, 4.554 kcal/g)-fed atherosclerotic ApoE-/- mice. Forty male ApoE-/- mice fed a HFD were randomly assigned to four groups: Control-Normoxia, Control-Hypoxia, SIT-Normoxia, and SIT-Hypoxia. The hypoxia protocol involved exposures to 11.2% oxygen three times (40 min each) per week. Key assessment parameters included plasma lipid profiles, skeletal muscle reactive oxygen species (ROS), protein carbonyls, key components of the Nrf2 antioxidant pathway, glutathione metabolism, and myokine-related markers. Compared with the control group, both hypoxia and SIT-Normoxia significantly reduced levels of ROS, protein carbonyls, and Vegfa165 mRNA expression in the skeletal muscle. Hypoxia alone enhanced the levels of GSH-synthesizing enzymes and promoted myokine production. SIT-Normoxia improved plasma lipid profiles, activated the Nrf2 pathway, enhanced the GSH system, and upregulated myokines. SIT under hypoxia further reduced ROS and Vegfa165 while increasing plasma HDL-C and levels of SOD1 protein in the skeletal muscle, but failed to synergistically activate the Nrf2 pathway or enhance GSH production. Paradoxically, both intervention combinations suppressed the mRNA expression of myokine precursor Fndc5, BAIBA-synthesizing enzyme Hadh and Hadha. Overall, six weeks of isolated hypoxia exposure or SIT training independently reduced oxidative stress and promoted beneficial myokine responses in the skeletal muscle of ApoE-/- mice fed a HFD. The wild-type (WT) mice fed a low-fat diet (LFD) was included to validate successful induction of hyperlipidemia, vascular remodeling, and skeletal muscle oxidative stress in ApoE-/- mice after six weeks of HFD feeding.

Keywords:  Atherosclerosis; Hypoxia; Myokine production; Oxidative stress; SIT; Skeletal muscle

DOI:  https://doi.org/10.1007/s00421-026-06350-2
Diabetes. 2026 Jul 24. pii: db251009. [Epub ahead of print]

GIP Acutely Blunts Insulin- and GLP-1-Induced Muscle Microvascular Perfusion.

Jia Liu, Changzoon Chun, Thomas K Sin, Fang Zhao, Kevin W Aylor, Nusrat J Tushi, Shengyi Sun, Zhenqi Liu.

ARTICLE HIGHLIGHTS: Skeletal muscle microvasculature is essential for nutrient delivery and metabolic regulation, but the vascular actions of glucose-dependent insulinotropic polypeptide (GIP) in muscle are unknown. We investigated whether GIP regulates skeletal muscle microvascular perfusion and interacts with insulin and GLP-1 signaling. GIP receptors are expressed in vascular endothelium, yet GIP alone does not increase muscle perfusion and instead antagonizes insulin- and GLP-1-mediated microvascular recruitment via possibly angiotensin II type 1 receptor-dependent endothelin-1/nitric oxide imbalance. GIP acts as a conditional regulator of skeletal muscle microvascular perfusion, revealing a novel mechanism of tissue-specific incretin regulation of nutrient partitioning.

DOI: https://doi.org/10.2337/db25-1009
Cell Metab. 2026 Jul 24. pii: S1550-4131(26)00290-1. [Epub ahead of print]

Circadian Clock Interaction with HIF1α Mediates Oxygenic Metabolism and Anaerobic Glycolysis in Skeletal Muscle.

Clara Bien Peek, Daniel C Levine, Jonathan Cedernaes, Akihiko Taguchi, Yumiko Kobayashi, Stacy J Tsai, Nicolle A Bonar, Maureen R McNulty, Kathryn Moynihan Ramsey, Joseph Bass.

DOI: https://doi.org/10.1016/j.cmet.2026.07.017