bims-moremu 2026-04-26 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–04–26
34 papers selected by
Anna Vainshtein, Craft Science Inc.

Lysophosphatidic acid mediates skeletal muscle fibrosis in denervation via activation of YAP/TAZ.
Phillyrin attenuates dexamethasone-induced skeletal muscle atrophy by inhibiting 15-PGDH.
Inhibiting muscle myosin super‑relaxation as a futile ATP cycle: a promising but narrow avenue for weight loss.
The pleiotropic impact of chaperone-mediated autophagy on skeletal muscle integrity.
Single Fiber Isolation Assay for the Assessment of Oxidative Myofiber Behavior.
A skeletal muscle atlas shows neuromuscular junction adaptations to growth and atrophy.
PHF2 regulates grip strength via demethylation at the promoter region of the Mef2c.
UNC45B Reduction With Aging: A Myofiber-Intrinsic Promoting Factor for Sarcopenia.
Vitamin B12 improves skeletal muscle mitochondrial biology in aged mice.
Current Progress in the Role of Ferroptosis in Skeletal Muscle Atrophy.
Gene Expression Profiles Reveal Altered Metabolic Signaling Pathway in Skeletal Muscle With Lipid Sensor Gpr120/Ffar4 Deficiency.
Myostatin in the pituitary-muscle axis: Roles in health and disease.
HuR-mediated regulation of mTOR mRNA stability promotes the commitment of satellite cells towards myogenesis.
Distinct distributions of myosin motor conformations during contraction of slow and fast skeletal muscle.
Fiber type-specific expression of LACTB leverages a function in oxidative metabolism.
Repeated application of passive mechanical stress produces selective metabolic and extracellular matrix adaptations in human skeletal muscle but does not prevent disuse-induced atrophy.
Single cell analysis of muscle contracture in cerebral palsy reveals pro-fibrotic and anti-myogenic stem cell populations with altered cell-cell interactions.
Fibrotic differentiation profile of skeletal and cardiac muscle fibroadipogenic progenitors in D2-mdx mouse.
B cell deficiency limits exercise capacity by remodeling liver glutamate metabolism.
Dexamethasone- and rapamycin-mediated mitochondrial dysfunction occurs independently of altered Yin Yang 1 expression in C2C12 myotubes.
Protective effects of irisin in sarcopenia: a promising treatment.
Evaluating skeletal muscle dysfunction and recovery in a zymosan model of critical illness in mice.
Cancer IDO1-Mediated Tryptophan-Kynurenine Metabolic Reprogramming to Drive Skeletal Muscle Atrophy and Cachexia Acceleration.
Acute Skeletal Muscle Activation Through Physical Exercise and Its Effects on Cognitive Performance and Neurobiological Markers in Adults: A Scoping Review.
In vivo systematic detection of the outcomes of CRISPR/Cas9 mediated DNA repair in skeletal muscle stem cells.
The unfolded protein response and its activation by insulin in muscle are not altered by obesity or type 2 diabetes.
Endothelial NOX1 Drives Obesity via Skeletal Muscle Mitochondrial Dysfunction.
Context-dependent roles of 11β-HSD1 in bone and skeletal muscle diseases.
Hypertension Drives Protein Lactylation and Vascular Dysfunction in Skeletal Muscle.
Combined Effects of Protein/Fat Deficiency and Disuse on Skeletal Muscle Mass and Function in Mice.
Targeting muscle-vasculature crosstalk in aging through the integrative roles of L-citrulline, leucine, and exercise: focus on muscle metabolism, vascular function, and sarcopenia prevention.
Melatonin attenuates mitochondrial apoptosis and improves mitochondrial quality by activating the AKT/BAD/BCL-XL signaling pathway, promoting oxidative muscle fiber formation.
APLNR reduction in kidney-muscle crosstalk in renal model recovered by exercise and STAT3 inhibition.
UFL1 deficiency impairs skeletal muscle development by activating PERK/eIF2α/ATF4/CHOP pathway-dependent apoptosis.

JCI Insight. 2026 Apr 22. pii: e198388. [Epub ahead of print]11(8):

Lysophosphatidic acid mediates skeletal muscle fibrosis in denervation via activation of YAP/TAZ.

Meilyn Cruz-Soca, Adriana Córdova-Casanova, Jennifer Faundez-Contreras, Nicolás W Martínez, Francesca Vaccaro-Rivera, Sebastián Bazaes-Astorga, Cristian Gutiérrez-Rojas, Felipe S Gallardo, Daniela L Rebolledo, Felipe A Court, Jerold Chun, Carlos P Vio, Soledad Matus, Juan Carlos Casar, Enrique Brandan.

  Lysophosphatidic acid (LPA) is a bioactive lipid that signals through G protein-coupled receptors (LPA1-6) and regulates multiple cellular processes, including fibrosis. Although LPA signaling has been implicated in fibrotic diseases in several organs, its role in skeletal muscle remains unclear. Here, we show that LPA/LPA1 signaling promotes fibrogenesis after sciatic nerve transection. Denervation induces differential expression of LPA signaling axis components and a transient early increase in intramuscular LPA levels. Pharmacological inhibition of LPA1/3 with Ki16425, or genetic deletion of LPA1, reduces extracellular matrix accumulation and expansion of fibro/adipogenic progenitors (FAPs) in denervated muscle. Although LPA blockade suppresses atrophy-related gene expression, it does not fully preserve myofiber size. Mechanistically, denervation increases YAP/TAZ expression, nuclear localization in FAPs, and transcriptional activity, effects that are attenuated by LPA axis inhibition. Furthermore, pharmacological inhibition of YAP/TAZ with verteporfin reduces fibrosis after denervation, supporting their role as critical downstream mediators. Finally, transient denervation activates the LPA axis, promotes muscle fibrosis, reduces axonal density in the sciatic nerve, and increases neuromuscular junction instability, effects reversed by Ki16425. Together, these findings identify the LPA/LPA1/YAP/TAZ pathway as a key driver of denervation-induced muscle fibrosis and a potential therapeutic target in neuromuscular disorders.

Keywords:  Cell biology; Fibrosis; Muscle biology; Signal transduction; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.198388
Biochem Biophys Res Commun. 2026 Apr 08. pii: S0006-291X(26)00463-8. [Epub ahead of print]818 153699

Phillyrin attenuates dexamethasone-induced skeletal muscle atrophy by inhibiting 15-PGDH.

Jin-Chan Liu, Ren-Ju Yang, Ya-Wen Liu, Fei He.

  Glucocorticoid-induced skeletal muscle atrophy is characterized by progressive loss of muscle mass and function, yet effective pharmacological interventions remain limited. Prostaglandin E2 (PGE2) plays an important role in maintaining muscle regeneration, and its degradation is primarily controlled by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Here we investigated whether phillyrin, a natural lignan compound, protects against dexamethasone (DEX)-induced muscle atrophy in mice. Phillyrin treatment significantly attenuated DEX-induced reductions in muscle mass and improved grip strength and motor endurance. Histological analysis showed that phillyrin alleviated myofiber atrophy and preserved mitochondrial ultrastructure. Mechanistically, phillyrin suppressed the upregulation of 15-PGDH and restored intramuscular PGE2 levels, accompanied by recovery of EP4 signaling. These changes were associated with inhibition of FOXO3a-mediated proteolysis and partial restoration of mTOR and PGC-1α signaling in skeletal muscle. Collectively, these findings indicate that phillyrin protects against glucocorticoid-induced muscle atrophy, potentially through modulation of the 15-PGDH/PGE2 pathway. These findings suggest that phillyrin may represent a potential therapeutic candidate for the treatment of glucocorticoid-induced skeletal muscle atrophy.

Keywords:  15-PGDH; EP4; PGE(2); Phillyrin; Secondary sarcopenia

DOI:  https://doi.org/10.1016/j.bbrc.2026.153699
J Physiol. 2026 Apr 22.

Inhibiting muscle myosin super‑relaxation as a futile ATP cycle: a promising but narrow avenue for weight loss.

Julien Ochala.



Keywords:  heart; myosin; obesity; skeletal muscle; weight loss

DOI:  https://doi.org/10.1113/JP291232
Autophagy. 2026 May;22(5): 877-880

The pleiotropic impact of chaperone-mediated autophagy on skeletal muscle integrity.

Dimitra Dialynaki, Daniel J Klionsky.

  Skeletal muscle is a fundamental tissue as it is found throughout the body, sustains posture, and produces movement. Yet, skeletal muscle disorders, such as myopathies, affect a large percentage of the population, degrading an individual's quality of life. A recent study links myopathy progression to the decline in chaperone-mediated autophagy that occurs during aging. Underscoring the importance of a balanced CMA pathway in maintaining skeletal muscle function and integrity, the study also provides mechanistic insights into the pathways that are dysregulated due to defective CMA and presents an approach to reverse the age-dependent decline in this process.Abbreviations: ATP2A1, ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1; CMA, chaperone-mediated autophagy; HSPA8, heat shock protein family A (Hsp70) member 8; LAMP2A, lysosomal associated membrane protein 2A.

Keywords:  Aging; calcium homeostasis; chaperone-mediated autophagy; mitochondrial homeostasis; myopathy; skeletal muscle

DOI:  https://doi.org/10.1080/15548627.2026.2627051
J Vis Exp. 2026 Mar 31.

Single Fiber Isolation Assay for the Assessment of Oxidative Myofiber Behavior.

Huascar Pedro Ortuste Quiroga, Yoshitaka Mita, Yasuko Manabe, Nobuharu L Fujii, Teng Hu.

Skeletal muscle is composed of multinucleated myofibers whose integrity and function are essential for movement and overall health. In neuromuscular disorders, muscle groups can be affected differentially across disease types and stages, making it important to isolate viable single fibers from representative muscles for mechanistic studies. The objective of this protocol is to provide a reliable method for isolating a high yield of intact single myofibers from the murine soleus (SOL) muscle, which is challenging to dissociate due to fiber length and fragility. By optimizing collagenase concentration and digestion time, the protocol minimizes fiber loss and preserves viability during dissociation. The optimized workflow markedly reduces residual tissue attachment to isolated fibers, thereby limiting carryover of non-fiber cells and minimizing cross-cell contamination. This technique is suitable for single-fiber analyses as well as satellite cell isolation and subsequent expansion under conditions with minimal contamination. Using this optimized workflow, we routinely obtain ~300-500 intact SOL-derived single myofibers that can be immunolabelled with high efficiency and also yield a high-quality satellite cell population with minimal fibroblasts contamination. Using comparative analyses with Extensor Digitorum Longus (EDL) muscle we underscore the value of a tailored, muscle-specific approach to evaluating therapies in neuromuscular disease research, enabling candidate pharmaceutical interventions to be tested within small, tunable experimental windows.

DOI: https://doi.org/10.3791/70637
Dev Cell. 2026 Apr 21. pii: S1534-5807(26)00122-X. [Epub ahead of print]

A skeletal muscle atlas shows neuromuscular junction adaptations to growth and atrophy.

Silvia Campanario, Mercedes Grima-Terrén, Megan Rommelfanger, Stefania Dell' Orso, Xuesong Feng, Andrés Cisneros, Ignacio Ramírez-Pardo, Aina Calls-Cobos, Benjamin A Yang, Kyung Dae Ko, Esther García-Domínguez, Laura Pena-Couso, Grace Chou, Yuewen Zheng, Nasun Hah, Davide Randazzo, Alberto Pérez-Garcia, Tovah E Markowitz, Jose Milisenda, Iago Pinal-Fernandez, Andrew Mammen, Mari Carmen Gómez-Cabrera, Antonio L Serrano, Eusebio Perdiguero, Vittorio Sartorelli, Joan Isern, Pura Muñoz-Cánoves.

  The molecular basis underlying muscle atrophy, as it occurs during disuse or aging, and activity-induced hypertrophy remain poorly understood. A major challenge has been defining the diverse cellular and niche environments within skeletal muscle, which is mostly composed of multinucleated myofibers. Here, we present a single-nucleus and single-cell transcriptomic atlas, coupled with spatial profiling, of mouse limb skeletal muscle under resting conditions and during experimentally induced atrophy or hypertrophy. We identify condition-dependent shifts in muscle-resident cell populations and fiber-type-specific transcriptional responses. We also uncover extensive remodeling of the neuromuscular junction (NMJ), including the emergence of specialized synaptic myonuclei (SynM) and terminal Schwann cells (tSCs) associated with atrophic or hypertrophic states. High-resolution 3D imaging and spatial transcriptomics confirm these changes at the tissue level. Similar NMJ alterations are observed in denervated and exercised human muscle, supporting the translational relevance of this atlas for studying muscle plasticity and identifying therapeutic targets in muscle-related diseases.

Keywords:  Schwann cell; atrophy; cell atlas; hypertrophy; neuromuscular junction; skeletal muscle

DOI:  https://doi.org/10.1016/j.devcel.2026.03.010
iScience. 2026 Apr 17. 29(4): 115517

PHF2 regulates grip strength via demethylation at the promoter region of the Mef2c.

Taku Fukushima, Taiju Fujioka, Yuuki Imai, Satoru Masubuchi, Iori Sakakibara.

  Epigenetic modifications, including DNA methylation and histone modifications, play crucial roles in gene expression. Although histone H3 lysine-9 methylation (H3K9me) is a highly conserved repressive mark in heterochromatin regions, its specific function in skeletal muscle remains unclear. Here we demonstrate that PHF2, an H3K9me2 demethylase, is essential for skeletal muscle function, particularly in fast-twitch muscle fibers. Skeletal muscle-specific Phf2 knockout mice exhibited significantly reduced grip strength compared to controls. PHF2 differentially regulates protein metabolism and energy homeostasis between fast- and slow-twitch fibers, with more pronounced effects in fast-twitch muscles. Moreover, we found that PHF2 predominantly binds to transcription start site (TSS)-downstream regions of key genes, including Mef2c, which play a critical role in muscle function. Notably, PHF2 binding sites were enriched in pathways associated with protein regulation, cellular homeostasis, and muscle function. These findings reveal PHF2's broader regulatory role in maintaining muscle health and performance.

Keywords:  Biological sciences; Epigenetics; Genomics; Musculoskeletal medicine

DOI:  https://doi.org/10.1016/j.isci.2026.115517
Aging Cell. 2026 May;25(5): e70502

UNC45B Reduction With Aging: A Myofiber-Intrinsic Promoting Factor for Sarcopenia.

Taiga Mishima, Taiga Nagamune, Saori Tada, Daiki Watanabe, Nao Tokuda, Takashi Yamada, Akiko Hashimoto-Hachiya, Sayaka Higo-Yamamoto, Kohei Kido, Noriyuki Nagaoka, Aoi Ikedo, Yuuki Imai, Ryo Fujita, Seiya Mizuno, Satoru Takahashi, Katsutaka Oishi, Satoru Ato, Riki Ogasawara.

  Skeletal muscle mass and force decline with age, and the loss of muscle force precedes muscle atrophy. However, the underlying mechanisms remain unclear. Here, we investigated the role of the myosin co-chaperone, uncoordinated mutant number-45 myosin chaperone B (UNC45B), in regulating muscle mass and force. UNC45B expression decreased in mouse gastrocnemius muscle with age, particularly at 24 months old, and adeno-associated virus vector-mediated knockdown of Unc45b in 3-month-old mouse triceps surae muscle first reduced plantar flexor torque and then decreased gastrocnemius muscle mass. In addition, Unc45b knockdown in the triceps surae muscle resulted in lower bone mineral density. While maximum Ca2+-activated force in mechanically skinned fibers was not affected by Unc45b knockdown, Unc45b knockdown decreased the ratio of depolarization-induced force to the maximum Ca2+-activated force. We established tamoxifen-inducible skeletal muscle-specific Unc45b knockout (Unc45b imKO) mice to investigate whether the muscle atrophy and weakness due to the loss of Unc45b impacts metabolism and behavior. We found that Unc45b imKO reduced muscle mass and force at a whole-body level, but did not influence systemic glucose tolerance, insulin sensitivity, or the respiratory exchange ratio. However, Unc45b imKO mice reduced the amount of deeper non-rapid eye movement sleep, locomotor activity, and body temperature during the sleep phase. We conclude that UNC45B is essential for maintaining fast-twitch muscle mass and muscle force. In addition, Unc45b deficiency-mediated muscle loss is also associated with bone fragility, decreased body temperature, and impaired sleep quality.

Keywords:  chaperone; muscle atrophy; muscle force; sarcopenia

DOI:  https://doi.org/10.1111/acel.70502
Geroscience. 2026 Apr 24.

Vitamin B12 improves skeletal muscle mitochondrial biology in aged mice.

Abigail R Williamson, Angad Yadav, Wenxia Ma, Susan Schmitt, Shelby Rorrer, Lauren E Odom, Luisa F Castillo, Chloe T Purello, Olga V Malysheva, James Mobley, Martha Field, Anna E Thalacker-Mercer.

  Age-related skeletal muscle deterioration is a commonly reported disability among older adults, attributed to several factors including mitochondrial dysfunction, a major hallmark of aging. Therapies to attenuate or reverse mitochondrial decline are limited. Despite identified positive relationships between vitamin B12 (B12) and mitochondrial biology, the impact of B12 supplementation on skeletal muscle mitochondria, in advanced age, has not been examined. Thus, the impact of B12 supplementation on skeletal muscle mitochondrial biology was examined in aged female mice, given 12 weeks of B12 supplementation (SUPP) or vehicle control. In the mouse model, mitochondrial DNA and content were measured with PCR and citrate synthase activity, respectively; mitochondrial morphology was examined using transmission electron microscopy; mitochondrial function was examined using extracellular metabolic flux analysis; and proteins and pathway enrichment was identified with proteomics. The results demonstrated that SUPP in aged mice increased muscle mitochondrial content and improved morphology. Further, differentially expressed proteins were enriched in TCA cycle, OXPHOS, and oxidative stress pathways. This is the first study, to our knowledge, examining the impact of B12 supplementation on skeletal muscle mitochondrial biology in aged female mice. Results suggest that B12 supplementation improves mitochondrial biology in aged female mice.

Keywords:  Aging; Mitochondria; Sarcopenia; Skeletal muscle; Vitamin B12

DOI:  https://doi.org/10.1007/s11357-026-02264-1
Mediators Inflamm. 2026 ;2026(1): e3578349

Current Progress in the Role of Ferroptosis in Skeletal Muscle Atrophy.

Yu Chen, Yaqing Guo, Zibo Zhao, Siqian Yang, Biao Guo, Jian Xu.

  Atrophy of skeletal muscles, caused by multiple factors, including ageing, disuse, trauma and systemic diseases, is a major pathological condition that affects physical performance and systemic health by the loss of muscle function; in effect, weakening the whole body and leading to disabling conditions such as sarcopenia, frailty and increased fall risk. First reported in 2012 by Dixon et al., ferroptosis is a newly identified, distinct type of regulated cell death characterised by unique biochemical and morphological features and differs from classic apoptosis and necrosis. One hallmark feature of ferroptosis is its iron-dependence: excessive free intracellular iron deposits catalyse rapid peroxidation of membrane lipids, and release cytotoxic lipid peroxides, which interfere with cell integrity. In recent years, significant progress has been made in elucidating the roles of ferroptosis-related pathways in skeletal muscle atrophy. Building on these advances, our review systematizes skeletal muscle atrophy into three significant categories: ageing-, disuse- and systemic disease-induced atrophy. It carefully explores the involvement of ferroptosis in each of these atrophy models. Moreover, this review identifies and discusses key ferroptosis-related molecular targets for consideration, aiming to provide insights and possible future directions for developing therapies to treat muscle-wasting disorders.

Keywords:  ferroptosis; iron metabolism; lipid peroxidation; skeletal muscle atrophy; therapeutic targets

DOI:  https://doi.org/10.1155/mi/3578349
Genes Cells. 2026 May;31(3): e70114

Gene Expression Profiles Reveal Altered Metabolic Signaling Pathway in Skeletal Muscle With Lipid Sensor Gpr120/Ffar4 Deficiency.

Junfeng Shi, Taito Nakayama, Keiko Iida, Ryohei Shirai, Kenya Ueno, Ayako Hirata, Takeo Awaji, Kei Maruyama, Yuuki Kawamura, Yoshinori Takei, Akira Hirasawa.

Obesity is driven by a chronic imbalance between energy intake and energy expenditure (EE), and reduced EE has been implicated in its development. We previously demonstrated that deficiency of Gpr120/Ffar4, a lipid sensor, led to decreased EE. Since skeletal muscle is a major contributor to EE, we investigated whether Gpr120 is involved in skeletal muscle energy metabolism. We generated gene expression profiles of skeletal muscle in WT mice and Gpr120-deficient (KO) mice under a normal diet (ND) and a high fat diet (HFD) using microarray analysis and found that Gpr120 was associated with mitochondrial gene expression in response to HFD. We also discovered that the enrichment patterns of Gene Ontology (GO) terms in skeletal muscle of Gpr120-deficient mice were common to those of genetically modified mouse models associated with Ampk, Pgc1α, and Errγ, suggesting that these signaling factors may be involved in Gpr120-mediated signaling. Moreover, analyses including ChIP-seq of Errγ, morphological evaluation of mitochondria by electron microscopy, and measurements of mtDNA content and muscle strength demonstrated that Gpr120 was involved in regulating mitochondrial structure, gene expression, and skeletal muscle function. Together, our findings suggest that Gpr120 regulates mitochondrial homeostasis and function in skeletal muscle, possibly through signaling from distant organs.

DOI: https://doi.org/10.1111/gtc.70114
Endocrinol Diabetes Nutr (Engl Ed). 2026 Apr;pii: S2530-0180(26)00064-8. [Epub ahead of print]73(4): 501757

Myostatin in the pituitary-muscle axis: Roles in health and disease.

Pedro Iglesias.

  Myostatin (GDF-8), a TGF-β family myokine, regulates skeletal muscle growth and systemic metabolism and influences pituitary development and hormone secretion. This review summarizes experimental, translational, and clinical data linking myostatin to pituitary biology, including recent mouse evidence identifying muscle-derived myostatin as an endocrine driver of FSH synthesis via activin-type II/TGFBR1 signaling, with human confirmation pending. We analyze how pituitary disorders - growth hormone deficiency, acromegaly, hypercortisolism, central thyroid disease, central hypogonadism, and hypopituitarism - modify myostatin signaling, contributing to sarcopenia, anabolic resistance, and metabolic dysfunction. Across these conditions, human evidence remains limited and confounded by assay heterogeneity and comorbidities, as circulating myostatin often fails to mirror intramuscular changes. We propose an evidence framework emphasizing standardized assays (mature vs latent forms), longitudinal clinical cohorts, and integration of hormonal and functional endpoints. Myostatin remains a promising yet unvalidated biomarker and therapeutic target in endocrine-related muscle disease.

Keywords:  Desarrollo hipofisario; Disfunción muscular; Eje músculo–hipófisis; Enfermedades hipofisarias; Función del músculo esquelético; Hormonal regulation; Miostatina; Muscle dysfunction; Muscle–pituitary axis; Myostatin; Pituitary development; Pituitary diseases; Regulación hormonal; Skeletal muscle function

DOI:  https://doi.org/10.1016/j.endien.2026.501757
Cell Death Dis. 2026 Apr 21.

HuR-mediated regulation of mTOR mRNA stability promotes the commitment of satellite cells towards myogenesis.

Anne-Marie K Tremblay, Brenda Janice Sánchez, Bianca Colalillo, Souad Mubaid, Jason Sadek, Xian Jin Lian, Andrea Diaz Gaxiola, Sergio Di Marco, Imed-Eddine Gallouzi.

The RNA-binding protein HuR has been shown to promote the differentiation of cultured muscle cells into muscle fibers. HuR mediates this process by differentially regulating, at different stages of this process, mRNA targets encoding pro-myogenic factors. Despite these advancements, the role of HuR, in vivo, at various stages of the myogenic process and its impact on muscle formation and function remain elusive. Towards this end, we used the Myf5-Cre loxP system to knock out HuR at a stage where muscle precursor cells (satellite cells, SCs) commit to myogenesis. Using these mice, we found that the muscle-specific depletion of HuR impairs, physiologically, its formation during embryogenesis and in response to injury. These mice exhibited smaller skeletal muscles and reduced exercise endurance. We demonstrate, using these mice, that this effect is due, in part, to the HuR-mediated regulation of mTOR (mechanistic target of rapamycin) mRNA expression. Using primary and cultured muscle cells, we show that HuR associates with this message, regulating its stability. In doing so, HuR facilitates the commitment of satellite cells toward myogenesis, thus preventing their transdifferentiation toward adipogenesis. These findings thus identify HuR as a master regulator of SCs' commitment to myogenesis and uncover a potential target for manipulating muscle myogenic capacity in both normal and pathological conditions.

DOI: https://doi.org/10.1038/s41419-026-08759-1
J Physiol. 2026 Apr 20.

Distinct distributions of myosin motor conformations during contraction of slow and fast skeletal muscle.

Cameron Hill, Michaeljohn Kalakoutis, Alice Arcidiacono, Yanhong Wang, Emma Smith, Elisabetta Brunello, Luca Fusi, Malcolm Irving.

  Slow skeletal muscles maintain posture and produce graded movement at low metabolic cost. ATP utilization during fixed-end contractions is typically five times slower in slow muscles than in fast muscles from the same species. Mechanical measurements previously suggested that more myosin motors are attached to thin filaments during contraction of slow muscle, which seems incompatible with its high efficiency. We therefore used small-angle X-ray diffraction to provide a structural estimate of the fraction of myosin motors attached to thin filaments in slow muscle. The X-ray signals associated with myosin binding to actin indicate that only ∼10% of myosin motors are actin bound during fixed-end tetani of rat soleus slow muscles, compared with ∼25% in mouse extensor digitorum longus fast muscle. Moreover, X-ray signals associated with the helical organization of OFF myosin motors in the thick filaments show that ∼70% of myosin motors remain in the OFF conformation during tetanic contraction of rat soleus muscle, compared with only 30% in mouse extensor digitorum longus muscle. The much slower force development in soleus muscle also allowed clear separation of early structural changes in thick filaments on activation, some of which are distinct from those reported previously in fast muscles. Moreover, the early structural changes in soleus muscle have about the same amplitude in a twitch and a tetanus, suggesting that they are triggered by thin filament activation rather than thick filament stress and implying a fast signalling pathway between thin and thick filaments. KEY POINTS: The interaction between myosin motors and actin filaments in slow skeletal muscles maintains posture and produces graded movement at low metabolic cost. Mechanical studies have suggested that more myosin motors are attached to actin filaments during isometric contraction of slow than fast muscle, but this seems incompatible with its high efficiency. We used X-ray diffraction to show that there are fewer myosin motors attached to actin in slow muscle than in fast muscle because more motors are sequestered on the myosin filament. The slower force development in slow muscle also allowed us to isolate and characterize fast changes in myosin motor conformation associated with activation of the actin filaments.

Keywords:  muscle contraction; muscle regulation; myosin; skeletal muscle

DOI:  https://doi.org/10.1113/JP290232
Histochem Cell Biol. 2026 Apr 18. pii: 24. [Epub ahead of print]164(1):

Fiber type-specific expression of LACTB leverages a function in oxidative metabolism.

Kirsi-Marja Alanen, Rabah Soliymani, Jaakko Sarparanta, Satu Kuure, Kirsi Sainio, Zydrune Polianskyte, Muhammad Yasir Asghar, Ehsan Zangene, Annunziata Cascone, Maciej Lalowski, Peter Hackman, Johan Lundin, Dan Lindholm, Ove Eriksson.

  Skeletal muscle is composed of type I and type II fibers, each characterized by specific metabolic machinery. LACTB is a conserved mitochondrial protein implicated in lipid utilization and tumorigenesis, but its precise function in the cellular metabolism remains unclear. To gain novel insight into the functional role of LACTB, we investigated skeletal muscle to determine whether LACTB is segregated by fiber type. The expression of LACTB was determined by immunohistochemistry (IHC) and immunoblotting in skeletal muscle from healthy human subjects and the laboratory rat. The specificity of the antibody was assessed using recombinant human LACTB protein and endogenous LACTB in isolated mitochondria. IHC results were validated in a cellular model of myoblast differentiation using the C2C12 and L6 cell lines. The results demonstrated that LACTB is highly enriched in adult type I muscle fibers. During development, LACTB expression commences in type I primary myotubes at the time of their formation around week 20 of gestational age. LACTB expression in myoblasts is low but increases rapidly upon the induction of myotube differentiation. We conclude that LACTB plays a distinct role in mitochondria of type I fibers, most likely acting in oxidative metabolism related to energy use from lipids. This defines LACTB as a mitochondrial marker for type I fibers.

Keywords:  LACTB; Mitochondria; Muscle differentiation; Serine protease; Type I muscle fiber; Type II muscle fiber

DOI:  https://doi.org/10.1007/s00418-026-02476-8
Function (Oxf). 2026 Apr 21.

Repeated application of passive mechanical stress produces selective metabolic and extracellular matrix adaptations in human skeletal muscle but does not prevent disuse-induced atrophy.

Mohadeseh Ahmadi, Charles Seaman, Erik D Marchant, James Bartling, David Kofoed, Karisa Coombs, Chad R Hancock, Robert D Hyldahl.

  Exposure to mechanical stimuli can modulate skeletal muscle structure and metabolism, yet the extent to which repeated, isolated mechanical stress promotes adaptive remodeling in humans has not been defined. We investigated whether repeated percussive massage (PM)-a widely used but poorly validated therapeutic modality-induces beneficial skeletal muscle adaptations under ambulatory conditions and whether such adaptations confer resilience during limb disuse in humans. In a 6-week randomized trial, PM did not alter myofiber cross-sectional area, satellite cell abundance, or capillary density, but RNA-seq pathway analysis revealed enrichment of extracellular matrix (ECM) remodeling networks, which was supported by increases in expression of basement membrane and focal adhesion components. PM also reduced subcutaneous fat thickness and increased fatty acid-supported mitochondrial respiration while lowering mitochondrial H₂O₂ emission. In a separate 10-day immobilization study, PM failed to attenuate unloading-induced reductions in muscle size or strength. However, PM partially preserved fatty acid-supported respiratory capacity relative to a control group, indicating a selective metabolic resilience. Finally, in an acute mechanistic experiment, unilateral PM did not increase subcutaneous adipose tissue lipolysis, as interstitial glycerol concentrations rose similarly in treated and untreated limbs, suggesting that chronic reductions in subcutaneous fat thickness were not driven by lipolytic activation. Collectively, these findings demonstrate that repeated PM promotes targeted skeletal muscle metabolic adaptations, yet is insufficient to induce overt structural remodeling or prevent disuse-induced functional decline.

Keywords:  limb disuse; lipolysis; mechanical stimulation; mechanotransduction; percussive massage

DOI:  https://doi.org/10.1152/function.109.2025
Am J Physiol Cell Physiol. 2026 Apr 23.

Single cell analysis of muscle contracture in cerebral palsy reveals pro-fibrotic and anti-myogenic stem cell populations with altered cell-cell interactions.

Madison Stewart, Lin-Ya Hu, Taryn Loomis, Sarah E Brashear, Lizbeth M De La Torre, Anas Mohamed Sulthan, Marie Villalba, Jon R Davids, Yue Wang, Vedant A Kulkarni, Lucas R Smith.

  Development of muscle contractures are common in cerebral palsy (CP) and characterized by high muscle stiffness that limits function and mobility. However, the state of stem cells within contracture, particularly muscle stem cells and fibro-adipogenic progenitors, are largely unknown. This study leverages single cell RNA sequencing technology to determine how specific cell types are altered in the contracture environment. Skeletal muscle biopsies were collected from children with CP or typically developing (TD) children undergoing surgery. The 10X Genomics platform was used on tissue from n=3 patients per condition. Significant changes in CP compared to TD were investigated within individual cell types for differentially expressed genes, gene ontologies, cell subpopulations and predicted interactions. CP muscle stem cells demonstrated significant upregulation of fibrotic genes and down regulation of myogenic genes compared to typically developing. Fibro-adipogenic progenitors in CP showed the emergence of a significant proportion of a highly profibrotic subpopulation, leading to the most dramatically up-regulated genes in CP also being extracellular matrix constituents. Interacting signals between fibro-adipogenic progenitors, muscle stem cells, and immune cells were identified that support contracture progression. Contracture reduces myogenic muscle stem cells and enhances fibrotic signals in muscle stem cells and fibro-adipogenic progenitors that perpetuate contracture. The study reveals specific genes and signaling pathways as therapeutic targets to reduce muscle contracture in children with CP.

Keywords:  Cerebral palsy; Fibro-adipogenic progenitor; Fibrosis; Muscle Satellite Cell; Single cell RNA sequencing

DOI:  https://doi.org/10.1152/ajpcell.00808.2025
J Neuromuscul Dis. 2026 Apr 24. 22143602261441956

Fibrotic differentiation profile of skeletal and cardiac muscle fibroadipogenic progenitors in D2-mdx mouse.

Hiroyori Fusagawa, Justin Lau, Sankalp Sharma, Mengyao Liu, Yusef Samimi, Gabriel Franchet-Schaer, Ashley Fang, Minami Fusagawa, Hubert Kim, Brian T Feeley, Xuhui Liu.

  Muscle fibrosis is a key pathological feature of Duchenne muscular dystrophy (DMD) and is closely associated with disease progression. Fibroadipogenic progenitors (FAPs) are major contributors to fibrosis, yet the precise mechanisms remain unclear. To investigate FAP dynamics and lineage specification, we generated dual-reporter mice (PRURD2) by crossing D2.B10-Dmdmdx/J (D2-mdx) mice with FAP and brown/beige adipose tissue (BAT) reporter lines. Corresponding control mice (PRURDBA) were established on the DBA/2J background. At 12 months, heart, diaphragm, and tibialis anterior (TA) muscles were collected for histological analysis. FAPs were isolated via FACS and subjected to single-cell RNA sequencing. PRURD2 mice exhibited increased fibrosis across all muscles compared to controls (p < 0.01) and a significant rise in PDGFRα-GFP + FAPs (p < 0.05). UMAP clustering identified 11 distinct FAP subpopulations, with the fibrosis-associated CD55 cluster enriched in PRURD2 mice. Pseudotime analysis showed lineage progression from progenitor clusters toward the fibrogenic CD55 cluster. CellChat analysis indicated increased interactions in PRURD2 mice involving fibrosis-related pathways like COLLAGEN, TGF-β, WNT, NOTCH, and ANGPTL. Additionally, fibrosis-related signaling pathways such as THY1, TWEAK, EPHA, EPHB, and SEMA6 showed increased interactions among FAP clusters in PRURD2 mice. Differential gene expression analysis revealed top upregulated genes including Cxcl13, Cxcl3, Ly6d, Klk1, Fgf23, Serpinb2, Mmp13, Ccl17, Postn, and Adam12. PRURD2 mice develop severe fibrosis in skeletal and cardiac muscle, driven by FAP-induced signaling pathways and genes. This model is valuable for understanding muscle fibrosis in DMD and developing anti-fibrotic therapies.

Keywords:  duchenne muscular dystrophy; fibroadipogenic progenitors (FAPs); muscle fibrosis; scRNAseq; skeletal muscle

DOI:  https://doi.org/10.1177/22143602261441956
Cell. 2026 Apr 17. pii: S0092-8674(26)00340-5. [Epub ahead of print]

B cell deficiency limits exercise capacity by remodeling liver glutamate metabolism.

Youxiang Mao, Ziyan Xia, Xu Pan, Wenjun Xia, Peng Jiang.

  B cells are an essential component of humoral immunity, and B cell depletion therapies have clinically succeeded in eliminating cancerous B cells and treating autoimmune diseases. Here, we report an immune-independent function of B cells that spatially and metabolically drives exercise capacity. During exercise, B cell deficiency reduces transforming growth factor (TGF)-β1 production, which alters hepatic glutamate metabolism and decreases blood and muscle glutamate. Mechanistically, B cell-derived TGF-β1 transcriptionally upregulates hepatic glutaminase 2 (GLS2) and solute carrier family 7 member 5 (SLC7A5) expression, increasing glutamine catabolism and thus glutamate production in the liver. The resulting increase in glutamate fosters skeletal muscle calcium oscillations, calmodulin-dependent protein kinase (CaMK) kinase activity, and mitochondrial biogenesis, thereby improving exercise performance. Thus, we identify a metabolite-driven liver-muscle connection that regulates exercise capacity, linking B cell function to skeletal muscle calcium signaling via alteration of hepatic glutamate metabolism.

Keywords:  B cells; TGF-β1; exercise capacity; hepatic glutamate metabolism; immune-independent regulation; immunoexercise; skeletal muscle function; transforming growth factor

DOI:  https://doi.org/10.1016/j.cell.2026.03.039
Biochimie. 2026 Apr 20. pii: S0300-9084(26)00098-2. [Epub ahead of print]

Dexamethasone- and rapamycin-mediated mitochondrial dysfunction occurs independently of altered Yin Yang 1 expression in C2C12 myotubes.

Alexa J Klein, Kipton B Travis, John M Zimmerman, Roger A Vaughan.

  Skeletal muscle is an indispensable tissue and loss of skeletal muscle mass and function can severely impact quality of life. Dexamethasone-treated C2C12 myotubes are an increasingly common model for studying skeletal muscle pathology (such as atrophy). While many features of this model are well-established (reduced myotube size, reduced anabolic signaling, and increased atrophic signaling), the mechanisms by which dexamethasone leads to mitochondrial dysfunction are less explored. This work assessed the effect of dexamethasone-mediated mitochondrial dysfunction on Yin Yang 1 (YY1) expression. YY1 interacts with various signaling pathways, including the mechanistic target of rapamycin (mTOR) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (Ppargc1a/PGC-1α), all of which have been shown to be down-regulated following dexamethasone treatment.
METHODS: C2C12 myotubes were treated with dexamethasone at either 50μM or 100μM, or rapamycin at 100nM, or DMSO vehicle control for up to 24 hours. Mitochondrial function was assessed by measuring oxygen consumption, mitochondrial content was measured using fluorescent staining, and related protein expression was determined via Western blot.
RESULTS: As expected, both dexamethasone and rapamycin independently reduced mitochondrial function and content. However, despite reduced mTOR activity, neither dexamethasone (at either concentration) or rapamycin had any effect on YY1 expression.
CONCLUSION: Given the interplay between YY1 and metabolic signaling cascades, we hypothesized dexamethasone would down-regulate YY1 as part of a milieu of depressed metabolism. However, because we observed reduced mitochondrial function and content independent of changes in YY1 abundance and activity, it appears that altered YY1 abundance is not a vital contributor during dexamethasone-mediated mitochondrial dysfunction.

Keywords:  Mitochondrial dysfunction; Yin Yang 1; atrophy; myotube

DOI:  https://doi.org/10.1016/j.biochi.2026.04.007
J Orthop Translat. 2026 May;58 101090

Protective effects of irisin in sarcopenia: a promising treatment.

Yixiao Chen, Guoqing Li, Feng Gao, Ruijiang Li, Minghui Yang, Yufeng Ge, Xinbao Wu.

  Sarcopenia is an age-related progressive muscle degeneration condition characterized by loss of muscle mass, muscle strength, and poor physical function. Its prevalence and mortality rates continue to rise with advancing age, significantly impairing patients' quality of life. The pathogenesis of sarcopenia involves multiple pathophysiological processes, including imbalanced protein catabolism, cell death, mitochondrial dysfunction, and various cellular signaling pathways. Therefore, it is crucial to identify potential therapeutic targets and treatments for sarcopenia. As an exercise-induced myokine, irisin has shown great potential in maintaining skeletal muscle health. In this review, we focus on the relationship between irisin and sarcopenia, delving into existing research to elucidate irisin's mechanisms of action in sarcopenia-including its effects on protein catabolism, cell death, mitochondrial dysfunction, cellular signaling, and muscle cell proliferation and differentiation. We provide insights into irisin as a therapeutic intervention for sarcopenia and provide essential evidence to support its clinical application in sarcopenia treatment. The Translational Potential of this Article . This review highlights the mechanism of action of irisin in sarcopenia and its potential as a therapeutic candidate for sarcopenia in the future.

Keywords:  Cell death; Irisin; Protein metabolic balance; Sarcopenia; Signaling pathway; Treatment

DOI:  https://doi.org/10.1016/j.jot.2026.101090
Dis Model Mech. 2026 Apr 24. pii: dmm.052712. [Epub ahead of print]

Evaluating skeletal muscle dysfunction and recovery in a zymosan model of critical illness in mice.

Amy J Bongetti, Annabel Chee, John H V Nguyen, Jin D Chung, Wenlan Li, Kristy Swiderski, Yasmine Ali Abdelhamid, Olav E Rooyackers, Marissa K Caldow, Gordon S Lynch.

  Muscle wasting and weakness are common complications associated with critical illness and admission to the Intensive Care Unit (ICU), that contribute to increased mortality and health deficits post-discharge. The mechanisms underlying ICU-acquired muscle weakness (ICU-AW) are incompletely understood and small animal models can help address this shortfall and provide experimental platforms for devising therapeutic strategies. We used a zymosan model to induce wasting, and weakness in C57BL/6J mice and evaluated recovery of hindlimb muscles and diaphragm at 4, 7, 14, and 28 days (D) after induction of critical illness, through extensive physiological and immunohistological analyses. Tibialis anterior (TA) muscles from zymosan treated mice exhibited atrophy and functional impairment at D4 and D7 with recovery at D14. In contrast, the DIA exhibited a delay in wasting and recovery from critical illness, with muscle fibre atrophy at D28 despite inflammatory cell infiltration from D4 and transient impairments in respiratory function. The zymosan mouse model provides important insights into mechanisms underlying the recovery from wasting and weakness after critical illness to better understand and treat ICU-AW.

Keywords:  Animal models; Critical illness; Inflammation; Intensive care; Muscle wasting; Muscle weakness; Sepsis; Skeletal muscle

DOI:  https://doi.org/10.1242/dmm.052712
J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70295

Cancer IDO1-Mediated Tryptophan-Kynurenine Metabolic Reprogramming to Drive Skeletal Muscle Atrophy and Cachexia Acceleration.

Leng Han, Lingjie Jing, Xinting Zhu, Ciqin Li, Lu Bai, Yang Fang, Yuxuan Zhou, Dingyuan Bai, Jin Lu, Yonglong Han, Cheng Guo, Shumin Zhou, Quanjun Yang.

   BACKGROUND: Cancer cachexia is a debilitating syndrome characterized by severe skeletal muscle wasting, which significantly impairs patient quality of life and survival. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in tryptophan (Trp) metabolism, is often upregulated in cancers, but its specific role in driving lung cancer-associated cachexia remains inadequately defined. This study investigated the mechanistic role of Ido1 in cancer cachexia and evaluated the therapeutic potential of its inhibition.
METHODS: We established Lewis lung carcinoma (LLC) models in C57BL/6 mice using wild-type, Ido1-overexpressing (Ido1-OE) and Ido1-knockout (Ido1-KO) cells. Muscle mass, tumour growth and metabolic changes were assessed in vivo. Transcriptomic and targeted metabolomic analyses were performed on muscle and serum samples. In vitro, we examined the effects of tumour-conditioned media, the Trp metabolite kynurenine (Kyn) and Trp supplementation on C2C12 myotube atrophy. In vivo experiments verified the efficacy of the Ido1 inhibitor palmatine hydrochloride (PAL). Molecular pathways were analysed via western blot and qPCR.
RESULTS: Compared to LLC mouse models, Ido1-OE significantly exacerbated tumour growth and cachexia, leading to a significant decrease in lean body weight, gastrocnemius and tibialis anterior muscle weights (p < 0.01, p < 0.0001, p < 0.001). Gastrocnemius muscle fibre cross-sectional area significantly decreased in the Ido1-OE group (p < 0.0001). Transcriptomic analysis revealed that Ido1-OE activated pro-inflammatory and protein degradation pathways (upregulating MuRF1/Atrogin1, p < 0.05) while suppressing anabolic signalling pathways (oestrogen pathways, p < 0.01). Metabolomics analysis revealed unique metabolic signatures in Ido1-OE mice: Trp depletion and Kyn accumulation. In vitro experiments demonstrated that Ido1-OE enhanced LLC cell proliferation and migration capabilities (p < 0.0001, p < 0.0001). Tumour-conditioned medium (TCM) derived from Ido1-OE tumours significantly induced C2C12 myotube atrophy (p < 0.01). Similarly, direct treatment with Kyn led to dose-dependent muscle fibre shrinkage, with significant atrophy observed at 30 μM (p < 0.01) and 100 μM (p < 0.0001). Notably, the myotube atrophy induced by Kyn was significantly reversed by the addition of supplemental Trp (p < 0.0001). Compared with the Ido1-OE group, PAL treatment reduced gastrocnemius and tibialis anterior atrophy (p < 0.01; p < 0.05). Mechanistically, PAL inhibited the mRNA expression levels of MuRF1/Atrogin1 (p < 0.0001, p < 0.001), as well as their corresponding protein levels (p < 0.0001, p < 0.0001). Furthermore, PAL restored the phosphorylation level of mTOR (p < 0.001), as well as the mRNA expression of myosin heavy chain (p < 0.01).
CONCLUSIONS: Our findings demonstrate that Ido1 accelerates muscle atrophy and cancer cachexia by driving a metabolic reprogramming centred on the Trp-Kyn pathway. Pharmacological inhibition of Ido1 with PAL effectively mitigates these effects, positioning Ido1 as a promising therapeutic target for treating cancer cachexia.

Keywords:  cancer cachexia; indoleamine 2,3‐dioxygenase 1; kynurenine; metabolic reprogramming; muscle atrophy; tryptophan

DOI:  https://doi.org/10.1002/jcsm.70295
Muscles. 2026 Mar 30. pii: 25. [Epub ahead of print]5(2):

Acute Skeletal Muscle Activation Through Physical Exercise and Its Effects on Cognitive Performance and Neurobiological Markers in Adults: A Scoping Review.

Sabine D Brookman-May.

  Physical exercise can influence cognitive performance and neurobiological processes, but evidence spans diverse modalities, intensities, and adult populations. Acute exercise represents a state of transient skeletal muscle activation that induces systemic signaling through metabolic, endocrine, and myokine-mediated pathways, which may contribute to neurocognitive modulation. To map the breadth of acute exercise-cognition research, characterize cognitive and biological outcomes, and identify consistent patterns and gaps. Studies of adults (≥18 years) involving a single exercise session or short microcycle (≤7 days) with pre-post assessment of cognition and/or neurobiological markers across any exercise modality (aerobic, resistance, high-intensity interval training/HIIT, combined, vibration, mind-body) were included. PubMed and CENTRAL were systematically searched, yielding 101 studies. Data were extracted using a structured framework capturing exercise modality, dose, cognitive domains, biomarkers, neuroimaging outcomes, population characteristics, and study design features. Most studies examined young adults (53%) or older adults (32%). Aerobic exercise predominated (62%), followed by resistance (18%) and combined modalities (12%). Moderate-to-vigorous aerobic exercise consistently improved executive function, processing speed, and working memory. Resistance exercise also enhanced executive function in several trials (31 studies). Neurobiological correlates included increases in Brain-Derived Neurotrophic Factor (BDNF), lactate, catecholamines, and prefrontal activation, though variability in sampling limited mechanistic conclusions. Acute exercise is consistently associated with improvements in executive function and processing speed across modalities. Standardized exercise protocols, biomarker timing, and cognitive assessments are needed to strengthen mechanistic synthesis.

Keywords:  acute exercise; brain-derived neurotrophic factor (BDNF); cerebrovascular function; cognitive performance; executive function; exercise physiology; functional near-infrared spectroscopy (fNIRS); high-intensity interval training (HIIT); muscle–brain crosstalk; myokines; neuromuscular activation; skeletal muscle

DOI:  https://doi.org/10.3390/muscles5020025
Mol Ther. 2026 Apr 20. pii: S1525-0016(26)00297-2. [Epub ahead of print]

In vivo systematic detection of the outcomes of CRISPR/Cas9 mediated DNA repair in skeletal muscle stem cells.

Liangqiang He, Yang Fu, Ziliu Wang, Qin Zhou, Hao Sun, Huating Wang.

CRISPR/Cas9 has revolutionized genome editing with broad therapeutic applications, yet its repair patterns in vivo remain poorly understood. Here, we systematically profile CRISPR/Cas9 editing outcomes at 95 loci using our established CRISPR/Cas9/AAV9-sgRNA system in skeletal muscle stem cells (MuSCs). Through comprehensive characterization of the repair outcomes, our findings demonstrate that the general rules governing CRISPR/Cas9-mediated editing in vivo largely align with those observed in vitro. Additional to the anticipated small editing indels such as MMEJ mediated deletions and NHEJ mediated templated insertions, we uncover a prevalent occurrence of large on-target modifications, including large deletions (LDs) characterized by microhomology (MH) and large insertions (LIs). Notably, the LIs comprise not only exogenous AAV vector integrations but also endogenous genomic DNA fragments (Endo-LIs). Endo-LIs preferentially originate from active genomic regions, with their integration shaped by three-dimensional chromatin architecture. By disrupting key components of the NHEJ and MMEJ repair pathways in vivo, we identify their distinct roles in regulating the large on-target modifications. Together, our work systematically profiles the CRISPR/Cas9 repair outcomes in vivo and offers valuable guidance for improving the safety of CRISPR/Cas9-based gene therapies.

DOI: https://doi.org/10.1016/j.ymthe.2026.04.032
Clin Sci (Lond). 2026 Apr 22. pii: CS20250639. [Epub ahead of print]

The unfolded protein response and its activation by insulin in muscle are not altered by obesity or type 2 diabetes.

Rikke Kruse, Jonas Møller Kristensen, Birgitte Falbe Vind, Stine Juhl, Jacob Volmer Stidsen, Rugivan Sabaratnam, Kurt Højlund.

  Insulin resistance in obesity and type 2 diabetes (T2D) is characterized by reduced insulin-stimulated glucose uptake, accumulation of triacylglycerol, mitochondrial dysfunction, and altered protein metabolism in skeletal muscle. This may involve disturbed endoplasmic reticulum (ER) homeostasis, leading to alterations in the unfolded protein response (UPR), and hence the protein folding capacity. Here, we investigated if markers of UPR activity are elevated in skeletal muscle in obesity and T2D, and to what extent insulin regulates these UPR markers. In a case-control design, we determined mRNA expression, protein abundance, and phosphorylation of key UPR markers in skeletal muscle biopsies obtained from patients with T2D, matched to glucose-tolerant individuals with obesity and lean individuals, before and after 4-h insulin infusion during a hyperinsulinemic-euglycemic clamp. The mRNA expression or protein abundance of GRP78, the canonical ER stress sensors (ATF6, PERK, and IRE-1α), several downstream UPR markers, and related markers of mitochondrial dynamics did not differ between groups. Insulin increased the mRNA expression of ATF6, ERN1 (encoding IRE-1α), XBP1, DDIT3 (encoding CHOP), and a marker of mitochondrial fission DNM1l (encoding DRP1), as well as eIF2α Ser51 phosphorylation in skeletal muscle in all groups (all p<0.05), with no between-group differences. Our results demonstrate that markers of UPR activity are not elevated in skeletal muscle in obesity or T2D. Interestingly, insulin increases the expression of UPR markers and activates eIF2α, which is necessary for increasing the protein folding capacity of ER in muscle, and these responses are intact in obesity and T2D.

Keywords:  ER stress; Insulin; Obesity; Skeletal muscle; Unfolded protein response; type 2 diabetes

DOI:  https://doi.org/10.1042/CS20250639
Circ Res. 2026 Apr 23.

Endothelial NOX1 Drives Obesity via Skeletal Muscle Mitochondrial Dysfunction.

Kai Huang, Yuanli Huang, Yuhan Zhang, Yixuan Zhang, Nicholas W Hatch, Julie K Freed, Hua Linda Cai.

   BACKGROUND: Presently, we investigated hypothesized roles and mechanisms of cell type-specific, selective activation of different vascular NOX (NADPH oxidase) isoforms in obesity and metabolic syndrome.
METHODS AND RESULTS: Expression of NOX1 (NOX isoform 1) was significantly upregulated in wild-type mice fed a high-fat diet. Global knockout of NOX1 (NOX1-/y), rather than of NOX2 (NOX isoform 2)/NOX4 (NOX isoform 4), markedly abrogated high-fat feeding-induced body weight/fat mass gain, preadipocyte differentiation, fatty liver, glucose intolerance, and insulin/leptin resistance. Intriguingly, endothelial-specific NOX1 knockout (Cdh5cre-cre-inducible NOX1flox/flox knockout/floxed mice [NOX1CKO]), rather than vascular smooth muscle-specific NOX1 knockout (Myh11cre-NOX1CKO), substantially alleviated obesity and metabolic syndrome. Consistently, endothelial-specific NOX1 knockin mice (Cdh5cre-cre-inducible NOX1flox/flox knockin/floxed) fed a high-fat diet displayed exaggerated metabolic disorders. Endothelial cell-specific knockout/knockin of NOX1 was confirmed using endothelial cell washout experiments. Food/water intakes were not different from corresponding controls in high-fat-fed NOX1-/y, Cdh5cre-NOX1CKO, or Cdh5cre-cre-inducible NOX1flox/flox knockin/floxed mice, indicating no difference in energy intake. Instead, spontaneous activity, exercise capacity, mitochondrial oxygen consumption/ATP production, skeletal muscle mitochondrial function (reactive oxygen species production and swelling activity), and mitochondrial cristae structure were all substantially improved in NOX1-/y or Cdh5cre-NOX1CKO mice, indicating augmented energy expenditure attributed to preserved skeletal muscle mitochondrial function. Supportively, Cdh5cre-cre-inducible NOX1flox/flox knockin/floxed mice displayed deteriorated exercise capacity and skeletal muscle mitochondrial dysfunction. Endothelium-dependent vasorelaxation was restored in high-fat-fed NOX1-/y or Cdh5cre-NOX1CKO mice, confirming improved endothelial function. RNA-sequencing identified 4 genes (Cntnap4 [contactin-associated protein-like 4], Sgsm1, Tll2, and Syt9) and 7 genes (Odf3l2, Col9a1 [collagen type IX alpha 1 chain], Cldn23, Atp5g2, Nkx6-3, Ntsr2, and Zfp69) significantly downregulated/upregulated in high-fat-fed Cdh5cre-NOX1CKO mice, among which Cntnap4 and Col9a1 linked to muscular disorders. Importantly, we observed marked upregulation of NOX1 in isolated coronary arteries from human patients with obesity.
CONCLUSIONS: Taken together, our data for the first time establish a novel and paradigm-shifting concept that endothelial NOX1 drives systematic metabolic phenotypes, via impairment in skeletal muscle mitochondrial dysfunction with novel genetic signatures. Tissue-specific targeting of endothelial NOX1 and novel candidate genes may prove to be robustly effective in treating obesity and metabolic syndrome.

Keywords:  NADPH oxidases; metabolic syndrome; mitochondrial diseases; muscle, skeletal; obesity; reactive oxygen species

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326768
Am J Transl Res. 2026 ;18(3): 2297-2310

Context-dependent roles of 11β-HSD1 in bone and skeletal muscle diseases.

Liyue Huo, Wei Sui, Shang Wang, Wei Zhu, Yanwei Yang, Xiaolin Zhang, Yubei Zhang, Xuefeng Wang.

  Bone and skeletal muscles are vital to human health, and diseases related to these tissues can place significant stress on patients, families, and society. The key enzyme regulating glucocorticoid metabolism, 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), is encoded by the HSD11B1 gene and can convert inactive cortisone into active cortisol. Recent studies have shown that 11β-HSD1 is a key enzyme in the pathogenesis of bone and skeletal muscle, with its function being strictly context-dependent. 11β-HSD1 inhibits osteoblast differentiation and activates osteoclast formation, contributing to glucocorticoid-induced osteoporosis (GIOP). 11β-HSD1 accelerates skeletal muscle atrophy by disrupting the stability of muscle proteins. It plays a dual role in anti-inflammation and bone protection, participating in polyarthritis; 11β-HSD1 also contributes to bone loss and anti-inflammation in rheumatoid arthritis (RA) through multiple pathways. Clarifying the context-specific mechanisms of 11β-HSD1 in bone and skeletal muscle diseases is critical for clinical translation. This review systematically summarizes the role of 11β-HSD1 in bone and skeletal muscle diseases, outlines its potential as a disease-specific therapeutic target, and provides new insights for precise treatment of these diseases.

Keywords:  11β-HSD1; glucocorticoids; osteoporosis; polyarthritis; rheumatoid arthritis; skeletal muscle atrophy

DOI:  https://doi.org/10.62347/DGHG9106
Hypertension. 2026 Apr 22.

Hypertension Drives Protein Lactylation and Vascular Dysfunction in Skeletal Muscle.

Milene T Fontes, Paul Townsend, Landon Butler, Juliana M Parente, Fênix A Araujo, Tiago J Costa, Gisele F Bomfim, Laena Pernomian, Wenbin Tan, Brandon N VanderVeen, E Angela Murphy, Ryan J Stark, Joshua T Butcher, Cameron G McCarthy, Camilla F Wenceslau.

   BACKGROUND: Emerging evidence suggests a critical interplay between skeletal muscle metabolism and vascular function in the context of hypertension. Elevated plasma lactate levels precede the onset of hypertension and are inversely associated with skeletal muscle mass, highlighting skeletal muscle atrophy and metabolic dysregulation as key contributors to cardiovascular dysfunction.
METHODS: Male and female Wistar rats and spontaneously hypertensive rats were studied. Skeletal muscle performance was evaluated using in vivo plantarflexion torque measurements. Femoral arteries with surrounding skeletal muscle were isolated to assess contractility and relaxation. Plasma and muscle lactate levels were quantified using colorimetric assays. Structural remodeling and mitochondrial function were assessed via wheat germ agglutinin staining, succinate dehydrogenase activity, and high-resolution respirometry. Protein lactylation was evaluated by mass spectrometry-based lactylated proteomics. Human translational relevance was examined using publicly available skeletal muscle transcriptomic data.
RESULTS: Spontaneously hypertensive rats exhibited skeletal muscle dysfunction marked by increased fatigability, reduced muscle mass, impaired mitochondrial activity, and elevated muscle lactate levels. Despite upregulation of oxidative markers, persistent lactate accumulation suggested a maladaptive metabolic shift. Proteomics revealed differential lactylation of key structural proteins (myosins, nebulin) and metabolic enzymes (Nampt, GAPDH [glyceraldehyde-3-phosphate dehydrogenase]). The anticontractile effect of skeletal muscle on femoral arteries was completely lost in spontaneously hypertensive rats, accompanied by impaired vascular relaxation and increased arterial lactylation. Human transcriptomic data supported parallel metabolic alterations in hypertension.
CONCLUSIONS: Hypertension disrupts skeletal muscle metabolic homeostasis and muscle-vascular communication, driven in part by persistent lactate accumulation and altered protein lactylation. Targeting lactate-mediated signaling may offer new therapeutic avenues for hypertensive vascular dysfunction.

Keywords:  animals; humans; myosins; rats; torque

DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.125.25665
Geriatr Gerontol Int. 2026 Apr;26(4): e70486

Combined Effects of Protein/Fat Deficiency and Disuse on Skeletal Muscle Mass and Function in Mice.

Koichi Toyoshima, Bo-Kyung Son, Miya Oura, Zehan Song, Michiko Nanao-Hamai, Sumito Ogawa, Masahiro Akishita.

BACKGROUND: Sarcopenia is driven by multifactorial insults, including undernutrition and disuse; however, the causal links between inadequate nutrition and the loss of muscle mass and strength remain unclear. This study aimed to establish mouse models of protein and/or fat deficiency and to investigate their interaction with disuse on skeletal muscle.
METHODS: Nine-week-old male C57BL/6J mice fed isocaloric diets for 8 weeks: normal chow (NC), low fat (LF), low protein (LP), or low protein and low fat (LPLF). Outcomes included body weight, grip strength test, gastrocnemius and soleus muscle weights, cross-sectional area (CSA) of gastrocnemius muscle fibers, and gastrocnemius muscle mRNA expression of ubiquitin-proteasome system (UPS) markers (atrogin-1, MuRF1) and inflammatory cytokines (TNF-α, IL-6, IL-1β). After the 8-week diet phase, a disuse model using bilateral hindlimb immobilization for 1, 3, or 7 days was applied under continued isocaloric feeding to assess diet-disuse interactions.
RESULTS: Compared with NC, the LF, LP, and LPLF groups showed reduced body weight, grip strength, muscle mass, and myofiber CSA. Upregulation of UPS-related genes was observed in LPLF, whereas the expression of inflammation-related genes did not differ from NC in LF, LP, and LPLF. When combined with immobilization, LP and LPLF diets further exacerbated the decreases in muscle mass and strength compared with NC, accompanied by increased expression of both UPS- and inflammation-related genes.
CONCLUSIONS: An animal model of diet-induced reduction in muscle mass and strength was established, which will be useful for investigating the effects of protein and fat deficiency on skeletal muscle. Elucidating the detailed molecular pathways involved remains an important goal for future research and may provide new insights into nutritional approaches to prevent or treat sarcopenia.

DOI: https://doi.org/10.1111/ggi.70486
Front Nutr. 2025 ;12 1739173

Targeting muscle-vasculature crosstalk in aging through the integrative roles of L-citrulline, leucine, and exercise: focus on muscle metabolism, vascular function, and sarcopenia prevention.

Xinyi Lin, Yarui Zhang, Jiangjiang Pu, Yubing Peng.

  Aging is characterized by a gradual deterioration in skeletal muscle mass, strength, and vascular functionality, which ultimately leads to the development of sarcopenia and the subsequent loss of physical autonomy. Nutritional and exercise-based interventions that specifically address this interplay may offer viable, non-pharmacological approaches to maintaining both muscular and vascular integrity. L-citrulline (CIT), recognized as a precursor to nitric oxide (NO), has been demonstrated to enhance endothelial functionality, improve oxygen transport, and increase muscle perfusion, while leucine has been shown to stimulate muscle protein synthesis. Furthermore, exercise serves to modulate both NO availability and anabolic signaling pathways, thereby amplifying the effects of these amino acids. Recent clinical and experimental research indicates that the concurrent administration of CIT and leucine supplementation, in conjunction with structured exercise regimens, yields superior enhancements in muscle mass, vascular reactivity, and physical performance compared to isolated interventions alone. The aforementioned synergistic effects are facilitated through a comprehensive regulation of mitochondrial biogenesis, alongside a reduction in inflammation and oxidative stress. This review consolidates existing empirical evidence regarding the collective contributions of CIT, leucine, and physical exercise in fostering healthy aging, while also delineating prospective research avenues for the formulation of personalized nutritional and physical strategies aimed at enhancing both muscular and vascular well-being in the elderly population.

Keywords:  L-citrulline; aging; cognitive frailty; exercise; leucine; muscle–vasculature; neurovascular coupling; successful aging

DOI:  https://doi.org/10.3389/fnut.2025.1739173
Int J Biol Macromol. 2026 Apr 20. pii: S0141-8130(26)02053-2. [Epub ahead of print] 152127

Melatonin attenuates mitochondrial apoptosis and improves mitochondrial quality by activating the AKT/BAD/BCL-XL signaling pathway, promoting oxidative muscle fiber formation.

Pengkang Song, Liwei Huang, Tianye Gong, Guoqing Zhao, Xiaolong Pan, Juan Xiong, Sirong Cheng, Ruigao Song, Xi Wang, Hongxia Li.

  Skeletal muscle fiber-type plasticity is crucial for systemic metabolic health and exercise capacity. While melatonin has been reported to possess various metabolic regulatory functions, whether and how it directly regulates muscle fiber-type transformation through specific molecular pathways remains unclear. This study aimed to investigate the effects of melatonin on skeletal muscle fiber type and to elucidate the underlying signaling pathways and molecular mechanisms. In vivo, mice were chronically supplemented with melatonin, and their exercise performance was assessed. Histological analysis, transmission electron microscopy for mitochondrial ultrastructure, measurement of key mitochondrial function indicators, and marker gene levels were performed. RNA-Seq was used to screen key target genes, and molecular mechanism validation was carried out using qPCR, Western blot, siRNA gene silencing, and the AKT inhibitor (AZD5363). The results showed that melatonin treatment did not alter mouse body weight but significantly enhanced their exercise endurance, accompanied by an increased proportion of oxidative muscle fibers and comprehensive enhancement of mitochondrial biogenesis and function. Transcriptomics and molecular validation identified BCL2L1 (encoding the BCL-XL protein) as a key downstream target of melatonin. Mechanistically, melatonin activated AKT, leading to phosphorylation of BAD, thereby relieving its inhibition on BCL-XL. The upregulated BCL-XL not only effectively suppressed the mitochondrial apoptotic pathway but also synergistically improved mitochondrial function. Both AKT inhibition and BCL-XL siRNA completely abolished all the beneficial effects induced by melatonin. In summary, this study reveals that melatonin suppresses mitochondrial apoptosis, enhances mitochondrial function, and promotes oxidative myofiber generation through the AKT/BAD/BCL-XL signaling pathway.

Keywords:  Apoptosis; BCL-XL, mitochondrial; Melatonin; Muscle fiber-type

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152127
Biochem Biophys Rep. 2026 Jun;46 102565

APLNR reduction in kidney-muscle crosstalk in renal model recovered by exercise and STAT3 inhibition.

Gabriel Pereira, Thabata Caroline de Oliveira Santos, Sofía Tomaselli Arioni, Pietra Mancini Seibt, Emily Pereira Dos Santos, Luana Fortuna, Rodrigo Lazzarotto, Matheus Felipe Zazula, Juan Sebastian Henao Agudelo, Débora Tavares de Resende E Silva, Elizabeth Cristina Perez Hurtado, Katya Naliwaiko, Ricardo Fernandez, Danilo Cândido de Almeida, Rafael Luiz Pereira.

  Current evidence show that exercise has beneficial effects on skeletal muscle function in individuals with chronic kidney disease (CKD). The STAT3 signaling pathway and the apelin axis (apelin receptor, APLNR- and ligands, -apelin and/or -elabela), participate in the processes of kidney inflammation and fibrosis and both may be involved in muscle wasting during CKD. Herein we report that STAT3 pathway and APLNR are in fact involved in the muscle impairment concomitant to CKD in experimental model and in adult individuals with CKD. Male BALB/c mice were first submitted to an 8-week ladder climbing resistance training (RT) protocol and further were submitted to doxorubicin-induced experimental CKD with or without use of the STAT3 inhibitor (Stattic). The GSE157712 dataset was used to assess the muscle transcriptome profile of CKD patients. Bioinformatics' analysis of gene set enrichment analysis (GSEA) and gene ontology (GO) were performed and the APLNR was found to be a central component of muscle response over kidney stress. Mice from the RT protocol showed a protective effect of blocking STAT3 against kidney and muscle injury markers, while both CKD individuals and CKD mice reported alterations in the APLNR muscle expression. In conclusion, the muscle tissue function is affected during CKD, which can be attenuated by a protective and synergistic effect of exercise and STAT3 inhibition. Thus, APLNR appears as a key gene associated with muscle dysfunction in CKD patients and its muscle expression can be regulated by resistance exercise.

Keywords:  Apelin receptor (APLNR); Bioinformatics; Doxorubicin; Muscle loss; Resistance training; STAT3

DOI:  https://doi.org/10.1016/j.bbrep.2026.102565
Cell Signal. 2026 Apr 20. pii: S0898-6568(26)00202-0. [Epub ahead of print] 112550

UFL1 deficiency impairs skeletal muscle development by activating PERK/eIF2α/ATF4/CHOP pathway-dependent apoptosis.

Junjie Xu, Mali Guo, Ping Li, Fengwei Li, Kang Zhou, Fanghui Chen, Yafei Cai.

  Ubiquitin-like modifier 1 ligating enzyme 1 (UFL1), the essential E3 ligase in the UFMylation system, plays a crucial yet undefined role in skeletal muscle development. In this study, our primary objective was to elucidate the function and molecular mechanism of UFL1 in myoblast survival and myofiber development. UFL1 deficiency in mice exacerbated ultra structural damage in myofibers and significantly increased myoblast apoptosis both in vivo and in vitro, as evidenced by upregulation of Cleaved Poly (ADP-ribose) polymerase (cleaved PARP), Cleaved Cysteinyl aspartate specific proteinase 3 (cleaved Caspase-3), and BCL2-associated X protein (BAX), alongside downregulation of B-cell lymphoma 2 (BCL2). Mechanistically, UFL1 knockout robustly activated the ER stress response, characterized by a significant increase in mRNA levels of Glucose-regulated protein 78 (GRP78), Activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), as well as specific activation of the Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)/Eukaryotic translation initiation factor 2 subunit alpha (eIF2α)/ATF4/CHOP signaling axis. Conversely, UFL1 overexpression effectively suppressed this pathway and reduced apoptosis. Notably, treatment with the PERK inhibitor GSK2606414 successfully reversed the UFL1 deficiency-induced upregulation of p-PERK, p-eIF2α, ATF4, and CHOP and rescued the apoptotic phenotype. Our study demonstrates for the first time that UFL1 is a critical regulator for maintaining myoblast survival and normal myofiber development, acting partly through suppressing the PERK-mediated ER sress. These findings provide novel insights into the pathogenesis of muscle developmental disorders and suggest UFL1 as a potential therapeutic target.

Keywords:  Apoptosis; ER stress; PERK/eIF2α/ATF4/CHOP; Skeletal muscle; UFL1

DOI:  https://doi.org/10.1016/j.cellsig.2026.112550