bims-moremu 2026-06-07 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–06–07
38 papers selected by
Anna Vainshtein, Craft Science Inc.

Exercise training prior to and during cancer in mice preserves muscle mass, reduces tumour weight and suppresses molecular mediators of cachexia.
Skeletal muscle carnitine-acylcarnitine translocase deletion reveals vulnerability of oxidative muscle to fatty acid oxidation deficiency.
The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway.
Cytoplasmic region of beta-dystroglycan is essential for postsynaptic maturation and neuromuscular function in mice.
Axin1 Suppresses Muscle Regeneration by Promoting Myoblast Proliferation and Inhibiting Differentiation.
TDP-43 Sustains Satellite Cells to Maintain and Regenerate Skeletal Muscle.
Argonaute-2 slicing of Rtl1 promotes skeletal muscle development and postnatal survival.
Dietary monoalkyldiacylglycerol enhances muscle regeneration and induces type Ⅱb myofiber formation in cardiotoxin-injury mice.
Oxidative Stress and Diminished Mitochondrial Proteostatic Reserve Are Linked to Enhanced mtUPR Initiation in Aged Mouse Muscle.
Subsarcomeric regulation of thin and thick filaments in skeletal muscle myofibrils.
Mechanistic Basis of Sarcopenia and Nutritional Interventions for Combating Muscle Atrophy.
Sex-specific effects of fatiguing exercise on skeletal muscle passive mechanics are preserved in aging.
Aerobic exercise attenuates sarcopenia-related changes via TXNIP-associated modulation of apoptosis, inflammation and autophagy.
FBXL21 regulates diurnal proteostasis and stress response by targeting DNAJB6 and client proteins.
Mitochondrial Dysfunction in Myoblasts: A TSPO-Dependent Mechanism of Sarcopenia.
15-PGDH inhibition promotes muscle repair and strength recovery during GLP-1 receptor agonist-induced weight loss.
Myogenic dysregulation underlies tongue overgrowth in Beckwith-Wiedemann syndrome.
Loss of ACTA1 leads to delayed γ-AChR / ε-AChR switch in skeletal muscle in mice.
The epigenetic control of inflammaging in skeletal muscle and adipose tissue.
PEBP4 alleviates muscle wasting in lung cancer cachexia via KEAP1-NRF2-mediated redox homeostasis.
Measuring Calcium Efflux in Isolated Primary Mitochondria.
CILP2 exacerbates diabetes-induced muscle atrophy by over-activating skeletal muscle autophagy and inflammation via the P38 MAPK pathway.
Single-fiber morphometry and spatial transcriptomics reveal selective oxidative muscle fiber atrophy in non-metastatic breast cancer.
Mechanical Loading Induces the Radial Growth of Myofibrils and Myofibrillogenesis via an mTORC1-Dependent Mechanism.
Stress unmasks impaired endocrine coordination of glucose metabolism in dystrophin deficiency.
The Extracellular Matrix as a Central Regulator of Aging and Tissue Adaptation to Exercise.
Positive allosteric modulator selective for adult muscle nicotinic acetylcholine receptor.
Neither intracellular oxygen availability nor mitochondrial coupling explain lower oxidative capacity in older human vastus lateralis muscle in vivo.
Aerobic exercise partially improves the skeletal muscle phenotype in a model of heart failure with preserved ejection fraction in male mice.
A systematic review of molecular signaling in the muscle-brain-gut axis: exercise-induced myokines and microbial metabolites as key mediators.
Limited reproducibility of individual physiological adaptations to repeated endurance exercise training.
A transcription-driven model of scaled myonuclear accretion reveals a quantitative role for nuclear reserve capacity.
AMC-F1 regulates mitochondria-autophagy crosstalk independent of nutrient stress.
Muscle matters: A proposed algorithm to guide screening, assessment and management of poor muscle health in primary care.
Microbiota dysbiosis influences immune system and muscle pathophysiology of dystrophin deficient mice.
Association of Physical Activity With Changes in Skeletal Muscle Mass in Patients With Acute Stroke.
Effects of tyrosine kinase inhibitors on skeletal muscle metabolism: a link with muscle complaints.
MDBiomarkers: A queryable biomarkers database integrating multiple serum and tissue datasets for Duchenne muscular dystrophy.

J Physiol. 2026 Jun 04.

Exercise training prior to and during cancer in mice preserves muscle mass, reduces tumour weight and suppresses molecular mediators of cachexia.

Stavroula Tsitkanou, Pieter J Koopmans, Ana Regina Cabrera, Nathan Serrano, Calvin S Peterson, Ruqaiza Muhyudin, Zain B Malik, Micah Goeke, Eleanor R Schrems, Francielly Morena, Yuan Wen, Tyrone A Washington, Kevin A Murach, Nicholas P Greene.

  We investigated the prophylactic effects of exercise before and during cancer cachexia (CC) using a model designed to mimic endurance and resistance (i.e., concurrent) adaptations. Male and female Balb/c mice were randomly assigned to exercise or control groups whereby exercise groups were subjected to an 8-week voluntary progressive weighted wheel running (PoWeR) programme of habitual loading-mediated physical activity beginning at 8 weeks of age. At 16 weeks of age, mice were injected bilaterally with colon-26 adenocarcinoma (C26) cells or phosphate-buffered saline, and exercise training was maintained throughout disease progression. Twenty-five days post-tumour induction, we assessed whole-body and muscle phenotype, muscle protein synthesis, a priori targeted gene expression, and transcriptomic adaptations via RNA sequencing. PoWeR training preserved skeletal muscle mass across nearly all muscle groups and maintained tumour-free body and cardiac mass. Muscle mass adaptations related to running volume, and running distance relative to controls were not appreciably reduced by tumour status. Tumour burden was reduced after ∼11.5 weeks of PoWeR compared to sedentary, but this was not explanatory for muscle adaptations. PoWeR induced a faster-to-slower muscle fibre type transition in the gastrocnemius and suppressed key protein turnover markers (Redd1, Murf1, Atrogin, Ubc, Gadd45a) as well as the mitophagy-related marker Bnip3 in tumour-bearing muscle; 24 h muscle protein synthesis remained stable. PoWeR counteracted tumour-induced impairments in the muscle mitochondrial- and metabolic-related transcriptome. Collectively, physical activity prior to and during cancer preserves muscle mass, reduces tumour growth and mitigates molecular drivers of CC, underscoring its preventive and therapeutic potential as a lifestyle intervention. KEY POINTS: Cancer cachexia (CC) is a severe, multifactorial syndrome with limited effective therapies. Exercise training has emerged as a promising non-pharmacological approach to mitigate CC. Concurrent endurance and resistance training, initiated prior to and maintained during cancer, preserves skeletal muscle mass and reduces tumour burden in C26 colorectal tumour-bearing mice. Concurrent exercise training suppresses key mitochondrial- and metabolic-related molecular mediators of CC. Concurrent exercise training may serve as a preventive and therapeutic non-pharmacological strategy against CC.

Keywords:  PoWeR; colon cancer; concurrent exercise training; mitochondrial adaptations; mitophagy; muscle fibre type; progressive weighted wheel‐running; protein degradation

DOI:  https://doi.org/10.1113/JP290740
Am J Physiol Endocrinol Metab. 2026 Jun 01.

Skeletal muscle carnitine-acylcarnitine translocase deletion reveals vulnerability of oxidative muscle to fatty acid oxidation deficiency.

Filip Jevtovic, Nicholas C Williamson, Andrea S Pereyra, Molly Alexander, Espen E Spangenburg, Jessica M Ellis.

  Fatty acid oxidation (FAO) is a critical bioenergetic source for skeletal muscle with FAO impairments being linked to metabolic and contractile dysfunction. FAO is regulated by the carnitine shuttle in which FAO eligible fatty acids, in the form of acylcarnitines, are transported into the mitochondrial matrix by carnitine‑acylcarnitine translocase (CACT), yet the role of CACT in muscle in vivo has remained unexplored. To determine the requirement of CACT in muscle FAO and its influence on muscle mitochondrial bioenergetics, lipid profile, and muscle contractility, a novel conditional skeletal muscle-specific CACT knockout mouse (CactSk-/-) was generated. The requirement of CACT for long-chain FAO was confirmed by the complete abrogation of FAO flux in CactSk-/- muscle mitochondria. CACT was also required for the oxidative flux of medium-chain octanoyl-carnitine and acetyl-carnitine. CACT loss disrupted the lipid profile of skeletal muscle with long-chain acylcarnitine accumulation and shifted saturation profile of phospholipids away from saturated and highly unsaturated and towards di- and tri-saturated phospholipids. Elevated mitochondrial content was demonstrated by increased phospholipid content and mitochondrial staining in CactSk-/- muscles, occurring to a greater extent in oxidative muscles. Loss of CACT reduced muscle specific force production by ~70% in oxidative soleus muscle despite increased fiber size, and compensatory mitochondrial accumulation that preserved muscle metabolic capacity. These findings demonstrate the crucial role of CACT in muscle FAO and that oxidative muscles, in particular, undergo extensive lipid compositional, metabolic, and structural remodeling that coincides with impaired contractile function.

Keywords:  Skeletal muscle; carnitine-acylcarnitine translocase; fatty acid metabolism; muscle contraction

DOI:  https://doi.org/10.1152/ajpendo.00117.2026
Sci Adv. 2026 Jun 05. 12(23): eaed2478

The skeletal muscle slow myosin heavy chain regulates mammalian metabolic homeostasis through the NRF2 pathway.

Jaydeep Sharma, Somnath Mondal, Aparna Rai, Mahima Kumari, Anushree Bharadwaj, Sam J Mathew.

The mammalian skeletal muscle is central to metabolic homeostasis. Myosin heavy chains (MyHCs), key muscle contractile proteins, use energy from adenosine triphosphate hydrolysis to produce mechanical force, fundamental to muscle function. However, the link between MyHCs and metabolic regulation is unclear. Here, we demonstrate the role of Myh7, encoding the MyHC-slow protein, in regulating skeletal muscle function and metabolic homeostasis using skeletal muscle-specific knockout mice. The absence of MyHC-slow causes early postnatal skeletal muscle hypertrophy followed by atrophy, degeneration of the oxidative slow myofibers, alterations in fiber-type proportions, decreased force production, and muscle dysfunction. It also leads to impaired glucose utilization, insulin resistance, and reduced muscle GLUT4 levels, characteristic of type 2 diabetes. These are mediated through decreased levels of the antioxidant NRF2, elevated reactive oxygen species and mitochondrial dysfunction in the Myh7 knockouts, which can be rescued by activating NRF2 signaling via sulforaphane administration. Our findings link skeletal muscle contractility to metabolic homeostasis, identifying the NRF2 pathway as a key therapeutic target.

DOI: https://doi.org/10.1126/sciadv.aed2478
Proc Natl Acad Sci U S A. 2026 Jun 09. 123(23): e2600931123

Cytoplasmic region of beta-dystroglycan is essential for postsynaptic maturation and neuromuscular function in mice.

Jeffrey M Hord, Rolf Turk, Hajime Kusano, Erik P Rader, Sarah Burns, Zeita Gastel, Sally J Prouty, Liping Yu, Steven J Burden, Kevin P Campbell.

  The dystrophin-glycoprotein complex (DGC) provides structural integrity to the sarcolemma, and disruption of the DGC leads to muscular dystrophy. A core member of the DGC is dystroglycan (DG), which binds to extracellular ligands via α-DG and intracellular cytoskeleton via β-DG. Mutations in DAG1 or genes involved in the posttranslational processing of DG lead to a subset of neuromuscular diseases referred to as dystroglycanopathies. The importance of the α-DG extracellular interactions is well established; however, little is known about the significance of the β-DG intracellular interactions. Here, we investigate the importance of intracellular β-DG in neuromuscular health. Using a mouse that lacks a large intracellular region of β-DG (residues 777 to 893), we show that the deletion of cytoplasmic β-DG leads to skeletal muscle pathology accompanied by postsynaptic disruption. Our data show that within the specialized neuromuscular junction (NMJ), cytoplasmic β-DG is necessary for the localization of utrophin and rapsyn, and clustering of acetylcholine receptors. Moreover, we provide evidence that the postsynaptic abnormalities contribute to neuromuscular dysfunction in mice lacking the cytoplasmic region of β-DG. Further, using a mouse model that only lacks the C-terminal tail (residues 879 to 893) of β-DG, we demonstrate that skeletal muscle and NMJ health rely on β-DG residues 777 to 878. Together, our mouse models suggest that deletion of the cytodomain of β-DG surprisingly results in very severe neuromuscular pathophysiology in mice. Our results identify β-DG as a critical player in shaping and maintaining neuromuscular synapse architecture in vivo, thus further defining the molecular mechanisms underlying neuromuscular health.

Keywords:  dystroglycan; dystroglycanopathy; muscular dystrophy; neuromuscular junction; skeletal muscle

DOI:  https://doi.org/10.1073/pnas.2600931123
FASEB J. 2026 Jun 15. 40(11): e72016

Axin1 Suppresses Muscle Regeneration by Promoting Myoblast Proliferation and Inhibiting Differentiation.

Yingying Yue, Chang Zhang, Yang Guo, Lulu Zhang, Qiu Gu, Chunlei Zhou, Hong Mu, Wenyan Niu.

  Axin1, a scaffold protein, participates in maintaining glucose homeostasis and muscle function. However, the role of Axin1 in regulating skeletal muscle growth and regeneration remains poorly understood. This study aims to investigate the role of Axin1 in skeletal muscle proliferation, differentiation, and regeneration in the context of insulin resistance or obesity. We found that knockdown of Axin1 decreased the protein level of Cyclin D1 and increased the protein levels of MyoG and MyHC, but without effect on MyoD protein levels, to inhibit proliferation and promote differentiation of C2C12 muscle cells. Over-expression of Axin1 had the opposite effect. Chronic insulin treatment up-regulated Axin1 protein levels, which promoted myoblast proliferation and impaired differentiation in C2C12 muscle cells. Knockdown of Axin1 reversed these effects by inducing Cyclin D1-mediated cell cycle arrest and up-regulating MyoG expression. AAV-siAxin1 significantly increased the protein and mRNA levels of MyoG of basal and CTX-injured mouse skeletal muscle, without effect on Pax7 and MyoD. Skeletal muscle of HFD-fed mice and db/db mice have higher Axin1 and lower MyoG, eMyHC, and Desmin protein levels, which correlated with reduced early muscle regeneration in injured muscle. Knockdown of Axin1 reversed the effect of HFD on muscle regeneration. In summary, down-regulation of Axin1 inhibits muscle cell proliferation and promotes differentiation in basal and insulin resistant conditions, and promotes skeletal muscle regeneration in HFD mice.

Keywords:  Axin1; differentiation; insulin resistance; proliferation; regeneration; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202505000R
bioRxiv. 2026 May 23. pii: 2026.05.18.725568. [Epub ahead of print]

TDP-43 Sustains Satellite Cells to Maintain and Regenerate Skeletal Muscle.

Theodore E Ewachiw, Tenaya K Vallery, Shloka Dhar, Hayden Clarkson, Tiffany Elston, Haileigh Gay, Bradley B Olwin.

Skeletal muscle satellite cells, residing between the myofiber plasma membrane and the surrounding basement membrane, maintain and repair skeletal muscle throughout life. Typically quiescent, satellite cells can transition into a reversible alert state (G Alert ) that primes them for rapid activation to maintain or repair muscle. From G Alert , SCs can either re-enter quiescence or commit to the cell cycle, expand, and differentiate to fuse with existing regenerating myofibers. Exit from quiescence requires extensive post-transcriptional remodeling, including changes in RNA processing and RNA-binding protein activity. We show that TDP-43, an RNA binding protein, is essential for SC maintenance and muscle repair. Conditional deletion of TDP-43 in SCs caused a consistent and progressive loss of G Alert SCs even in uninjured muscle, leading to depletion of the SC pool. TDP-43 haploinsufficiency was sufficient to impair SC maintenance, indicating that both alleles are required. Integrative analysis suggests that TDP-43 supports expression of stress response-associated transcripts during the quiescent-to-G Alert transition, and that failure to mount this response contributes to SC apoptosis. Thus, we identified TDP-43 as a critical regulator of satellite cell survival as satellite cells activate and establish a TDP-43 requirement for maintaining and repairing skeletal muscle.

DOI: https://doi.org/10.64898/2026.05.18.725568
bioRxiv. 2026 May 24. pii: 2026.05.22.727060. [Epub ahead of print]

Argonaute-2 slicing of Rtl1 promotes skeletal muscle development and postnatal survival.

Nickolas Almodovar, Caroline Dunn, Benjamin Kleaveland.

Argonaute (AGO) proteins associate with small guide RNAs to bind and repress mRNA targets. AGO2 is the primary AGO slicer in mammals, cleaving RNAs that base-pair extensively to its guide RNA. Disrupting the slicing activity of AGO2 in mice causes neonatal lethality, however, the specific cell types and substrates that contribute to this lethality are not known. Through a combination of genetic, histologic, and molecular approaches, we identify retrotransposon-like-1 ( Rtl1 ) as a key AGO2 slicing substrate in placental endothelium and skeletal muscle, and show that AGO2 slicing in skeletal muscle, but not endothelium, is required for postnatal viability. Loss of AGO2 slicing causes cell-autonomous, pathologic changes in skeletal muscle, characterized by larger fibers, increased central nuclei, prominent central clearings, and induction of transcripts associated with an unfolded protein response. Forced expression of RTL1 in myoblasts induces a similar unfolded protein response, highlighting the importance of preventing excess Rtl1 during muscle development. Taken together, our findings demonstrate a critical role for AGO2 slicing in skeletal muscle development that is, at least in part, due to its repression of Rtl1 .

DOI: https://doi.org/10.64898/2026.05.22.727060
Biochem Biophys Res Commun. 2026 Jun 01. pii: S0006-291X(26)00840-5. [Epub ahead of print]827 154076

Dietary monoalkyldiacylglycerol enhances muscle regeneration and induces type Ⅱb myofiber formation in cardiotoxin-injury mice.

Kyosuke Imamura, Naoki Takatani, Masashi Hosokawa, Fumiaki Beppu.

  Monoalkyldiacylglycerols (MADG), ether-type glycerolipids found in deep-sea fish animals, promote myotube formation in C2C12 myoblasts. In this study, we investigated the effects of MADG on skeletal muscle regeneration in a mouse model of cardiotoxin-induced muscle injury. Male C57BL/6J mice were fed a diet supplemented with 0.5% MADG for 2 weeks, followed by cardiotoxin injection into the tibialis anterior muscle, and maintained on the experimental diets for up to an additional 2 weeks. The MADG diet increased the number and total area of myofibers 7 and 14 days post-injury compared with the normal diet group. mRNA levels of the myogenic regulatory factors MyoD and Myogenin increased, whereas those of inflammatory factors and satellite cell marker, remained unchanged. Immunohistochemical staining for myofiber type markers showed that dietary MADG promoted a shift toward a more fast-type phenotype, characterized by an increase in the number and proportion of MHC4-positive type Ⅱb fibers. In C2C12 myoblasts and mouse satellite cells, treatment with batyl alcohol, a MADG metabolite, increased Myh4 mRNA expression and decreased Myh2 mRNA expression. Overall, MADG promotes skeletal muscle regeneration and has the potential to induce a fast-twitch shift, accompanied by an increased proportion of type IIb myofibers during muscle repair. These results contribute to a better understanding of the regulation of myofiber types underlying skeletal muscle function and homeostasis.

Keywords:  Alkylglycerol; Fast-twitch myofiber; Monoalkyldiacylglycerol; Muscle regeneration; Muscle repair; Myogenesis

DOI:  https://doi.org/10.1016/j.bbrc.2026.154076
Aging Cell. 2026 Jun;25(6): e70573

Oxidative Stress and Diminished Mitochondrial Proteostatic Reserve Are Linked to Enhanced mtUPR Initiation in Aged Mouse Muscle.

Grant R Laskin, Baylah R Mazonson, LaDora V Thompson.

Mitochondrial dysfunction, impaired proteostasis, and reduced stress resistance and resilience are aging hallmarks. At the core of these hallmarks, the mitochondrial unfolded protein response (mtUPR) is a transcriptional pathway that restores mitochondrial proteostasis in response to proteotoxicity. Although the mtUPR is well studied in invertebrates and cell culture models, how the mtUPR is engaged in aged mammalian tissue is poorly defined. Here, we defined the extent to which repeated physical stress initiates mtUPR transcription in aged mouse skeletal muscle and assessed candidate regulatory mechanisms in vivo. Aged muscle exhibited reduced mitoprotective chaperone and protease availability and greater carbonylation of intermyofibrillar mitochondria relative to young muscle, suggesting diminished proteostatic reserve and increased oxidative burden. Short-term physical stress induced a greater initiation of mtUPR genes in aged muscle than young muscle, coinciding with reduced physiological reserve. Physical stress shifted ATF5 localization from the mitochondria to the nucleus in the muscle of both ages, whereas CHOP mRNA and nuclear localization were selectively elevated in aged muscle. Mechanistically, we show mitochondrial reactive oxygen species (mtROS) contribute to mtUPR initiation in aged skeletal muscle. Using in vivo ChIP-qPCR and in vitro knockdown/inhibition experiments, we provide support for CHOP as a redox-sensitive factor contributing in part to the enhanced mtUPR initiation in aged mouse muscle, potentially linked to JNK signaling. Collectively, these data suggest reduced mitochondrial proteostatic reserve and mtROS signaling in aged muscle contribute to an amplified mtUPR transcriptional response following repetitive physical stress, providing the foundation to explore the mtUPR in mammalian aging.

DOI: https://doi.org/10.1111/acel.70573
Proc Natl Acad Sci U S A. 2026 Jun 09. 123(23): e2535527123

Subsarcomeric regulation of thin and thick filaments in skeletal muscle myofibrils.

Kristina Sliogeryte, Luca Fusi.

  Muscle contraction relies on the coordinated activation of myosin motors from a folded-OFF state on the thick filament surface and their actin tracks on the thin filaments in response to calcium. Thick filaments contain distinct regulatory zones defined by the presence of myosin-binding protein C (MyBP-C) and titin super-repeats, but the control of myosin OFF/ON states within these zones has not been directly resolved. Here, we do so by fluorescence polarization microscopy (FPM) in myofibrils isolated from rabbit fast skeletal muscle. Using orientation-specific probes on myosin we show that folded-OFF motors are enriched in the MyBP-C-containing C zone in relaxed myofibrils, indicating that MyBP-C stabilizes the myosin OFF state in this filament domain. Under titin-based passive tension or partial calcium activation, active motors are enriched in the D zone at the filament tips, which lacks MyBP-C, suggesting that D-zone motors are activated at lower filament stress. Troponin probes further reveal that myosin enhances thin-filament activation in the region of filament overlap and drives the stress-dependent activation of the thin filament into adjacent nonoverlap regions. These findings uncover zone-specific control of myofilament activation within the sarcomere and establish FPM as a powerful tool for investigating disease-linked myofilament protein variants and therapeutic modulation.

Keywords:  muscle regulation; myosin; sarcomere; skeletal muscle; troponin

DOI:  https://doi.org/10.1073/pnas.2535527123
Curr Aging Sci. 2026 May 19.

Mechanistic Basis of Sarcopenia and Nutritional Interventions for Combating Muscle Atrophy.

Ritu Ladwal, Rajesh Dabur.

  Sarcopenia, the progressive and generalized loss of skeletal muscle mass and function with age, represents a major contributor to frailty, disability, and reduced quality of life in the elderly. Its pathophysiology is multifactorial, encompassing cellular, molecular, and systemic alterations. Mechanistically, sarcopenia is driven by satellite cell dysfunction, impaired regenerative capacity, mitochondrial decline, chronic low-grade inflammation, neuromuscular junction instability, and dysregulated proteostasis involving the ubiquitin-proteasome and autophagy- lysosome systems. Additional factors such as hormonal decline, oxidative stress, altered myokine signaling, and fiber-type transitions further exacerbate skeletal muscle atrophy. These interlinked processes collectively result in impaired muscle plasticity, reduced contractile strength, and progressive degeneration of type II fibers. Given the complexity of its mechanisms, nutritional interventions, particularly dietary supplements and natural products, have attracted considerable attention as potential modulators of sarcopenia. Hence, in the present study, the literature was scanned using standard databases and keywords related to 'natural products and diet used in sarcopenia' to identify research papers and reviews that were reviewed to compile the present review. It was found that some bioactive compounds, including polyphenols (such as resveratrol and curcumin), flavonoids (such as quercetin and catechins), omega-3 fatty acids, essential amino acids, and plant-derived adaptogens, exhibit antioxidant, anti-inflammatory, and mitochondrial- protective effects. These nutraceuticals not only counteract oxidative and inflammatory damage but also enhance anabolic signaling, mitochondrial biogenesis, and neuromuscular stability, thereby supporting muscle preservation and functional recovery. Emerging evidence suggests that combining such natural compounds with adequate protein intake and exercise may synergistically mitigate sarcopenia-induced skeletal muscle atrophy. This review consolidates current mechanistic insights into sarcopenia and critically evaluates the role of dietary supplements and natural products as promising, safe, and accessible interventions. Understanding the interplay between molecular pathways and nutritional modulation provides a foundation for developing effective strategies to combat age-related muscle decline.

Keywords:  Natural products; anti-inflammatory signalling; mitochondrial dysfunction; nutraceuticals; oxidative stress; sarcopenia; skeletal muscle atrophy; skeletal muscle regeneration.

DOI:  https://doi.org/10.2174/0118746098452491260515061005
bioRxiv. 2026 May 27. pii: 2026.05.22.727297. [Epub ahead of print]

Sex-specific effects of fatiguing exercise on skeletal muscle passive mechanics are preserved in aging.

Grace E Privett, Julissa Ortiz-Delatorre, Austin W Ricci, Karen Wiedenfeld Needham, Damien M Callahan.

Skeletal muscle function is central to the preservation of functional mobility. Given global shifts to an increasingly aged population, it is paramount that researchers and clinicians better understand the effectors of age-related functional decline. Muscle fatiguability acutely modifies skeletal muscle mechanics in ways that may affect joint stability. We have previously reported sex-specific reductions in cellular passive stress and modulus with fatigue in young males, but not females. Here, we assess whether older adults, who are more susceptible to fatigue during dynamic contractions, exhibit changes to cellular passive mechanics following fatiguing exercise. Muscle tissue biopsies were collected from 11 young and 11 older adults to measure passive stress and Young's Modulus at the single fiber and bundle level. Biopsy samples were acquired from rested muscle and immediately following intermittent maximal contractions to task failure. Fatigue was associated with persistent reduction in elastic modulus that was specific to male participants, regardless of age. In muscle fiber bundles, containing both myofibrillar proteins and the extracellular matrix, fatigue-induced changes in modulus were largely negated, with the only significant change observed in young females, who demonstrated enhanced modulus with fatigue. Taken together our findings suggest a preservation of sex-based differences in the acute response to fatigue across the adult lifespan when measured at the myofilament level. However, further research is needed to understand how and whether these findings translate to the whole tissue level.
New and noteworthy: Acute modifications to muscle tissue mechanics are poorly understood but may have important impacts on functional outcomes in at-risk populations. Our findings suggest myocellular mechanics respond to acute fatigue stress in a sex specific manner that persists across the lifespan.

DOI: https://doi.org/10.64898/2026.05.22.727297
Biochimie. 2026 May 29. pii: S0300-9084(26)00116-1. [Epub ahead of print]247 36-48

Aerobic exercise attenuates sarcopenia-related changes via TXNIP-associated modulation of apoptosis, inflammation and autophagy.

Xiaoqin Zhao, Qianyu Chen, Jiaqi You, Zhenxian An, Junping Li, Liang Yu, Zujie Xu.

  Sarcopenia is an age-related syndrome characterized by progressive loss of skeletal muscle mass, strength, and function, and represents a major challenge to healthy aging. Thioredoxin-interacting protein (TXNIP) has been associated with skeletal muscle alterations in sarcopenia, but its potential role in exercise-related adaptation remains unclear. In this study, naturally aged male Sprague-Dawley rats underwent a 10-week treadmill exercise intervention, and gastrocnemius muscle was examined using morphological, functional, and molecular approaches. Aging was associated with reduced relative gastrocnemius muscle mass, smaller myofiber cross-sectional area, impaired grip strength and endurance capacity, increased Atrogin-1 and MuRF-1 expression, enhanced apoptosis- and inflammation-related signaling, reduced Trx expression, increased TXNIP protein expression, detectable TXNIP-Trx and TXNIP-NLRP3 interactions, and altered autophagy-related markers. Aerobic exercise improved muscle morphology and endurance-related performance in aged rats, and was accompanied by reduced Atrogin-1 and MuRF-1 expression, coordinated changes in apoptosis-, inflammation-, and autophagy-related markers, reduced TXNIP expression at both mRNA and protein levels, decreased TXNIP-Trx and TXNIP-NLRP3 interactions, and altered PI3K/Akt/mTOR-related protein phosphorylation. These findings suggest that aerobic exercise may attenuate sarcopenia-related changes in aged skeletal muscle, potentially in association with TXNIP-related multi-pathway regulation.

Keywords:  Aerobic exercise; Apoptosis; Autophagy; Cell signaling; Inflammation; Sarcopenia; TXNIP

DOI:  https://doi.org/10.1016/j.biochi.2026.05.007
bioRxiv. 2026 May 22. pii: 2026.05.20.726545. [Epub ahead of print]

FBXL21 regulates diurnal proteostasis and stress response by targeting DNAJB6 and client proteins.

Ji Ye Lim, Jaebok Wi, Marvin Wirianto, Chorong Han, Sun Young Kim, Jane Nguyen, Sehyun Jung, Kristin Eckel-Mahan, Sung Yun Jung, Karyn A Esser, Zheng Chen, Seung-Hee Yoo.

Circadian regulation of proteostasis, a key determinant of muscle health, remains poorly understood. Here, we identified DNAJB6, an Hsp40 (DnaJ) co-chaperone, as a substrate of the circadian E3 ligase FBXL21. FBXL21 mediated the ubiquitination-dependent proteasomal degradation of both DNAJB6 and its client proteins including Desmin; causative mutations of DNAJB6 in myopathies, however, rendered resistance to FBXL21-directed degradation. Fbxl21 KO C2C12 cells displayed aberrant accumulation of Desmin, and showed aggravated cytoplasmic accumulation of TDP-43, another DNAJB6 client protein, in heat shock response. Under timed exercise as a physiological stressor, WT mice displayed robust diurnal rhythms in the levels of stress granule markers (G3BP1 and FUS) and TDP-43 as a function of exercise timing. In contrast, the Fbxl21 hypomorph Psttm mutant mice showed elevated expression of these proteins without exercise, which was exacerbated under exercise-induced stress conditions; importantly, these abnormalities were rescued by skeletal muscle-specific FBXL21 expression. Our study elucidates a novel diurnal regulatory mechanism of skeletal muscle proteostasis via FBXL21 as a chaperone-linked E3 ligase, highlighting the FBXL21-DNAJB6 axis as a potential therapeutic target for myopathies.

DOI: https://doi.org/10.64898/2026.05.20.726545
J Gerontol A Biol Sci Med Sci. 2026 Jun 02. pii: glag145. [Epub ahead of print]

Mitochondrial Dysfunction in Myoblasts: A TSPO-Dependent Mechanism of Sarcopenia.

Peng Zhang, Hongyu Zheng, Zhao Lin, Hanhao Dai, Minjuan Zhang, Linhai Yang, Zhibo Deng, Chao Song, Yibin Su, Rongsheng Zhang, Guoyu Yu, Jun Luo, Jie Xu, Fenqi Luo.

  Sarcopenia, the age-related loss of muscle mass and function, poses a significant health burden in aging societies. Although mitochondrial dysfunction is a recognized driver, the upstream molecular regulators remain poorly defined. Here, we identify the mitochondrial translocator protein (TSPO) as a novel negative regulator of myogenesis that is consistently upregulated in aged and sarcopenic muscle. Using gain- and loss-of-function approaches in C2C12 myoblasts, we show that TSPO overexpression disrupts mitochondrial homeostasis, impairs proliferation and differentiation, while TSPO knockdown produces opposite effects-establishing TSPO as a critical modulator of myogenic capacity. Mechanistically, TSPO suppresses the Wnt/β-catenin pathway, and this effect is partially mediated by ROS accumulation. Importantly, in vivo AAV9-mediated TSPO knockdown in aged mice not only restores mitochondrial integrity but also significantly improves muscle mass, strength, and exercise performance. Collectively, our findings uncover a TSPO-Wnt/β-catenin axis that links mitochondrial dysfunction to impaired muscle regeneration in aging. Targeting TSPO may offer a dual-action therapeutic strategy to combat sarcopenia by simultaneously enhancing mitochondrial bioenergetics and reactivating pro-myogenic signaling.

Keywords:  TSPO; Wnt/β-catenin signaling pathway; differentiation; proliferation; sarcopenia

DOI:  https://doi.org/10.1093/gerona/glag145
Proc Natl Acad Sci U S A. 2026 Jun 09. 123(23): e2606533123

15-PGDH inhibition promotes muscle repair and strength recovery during GLP-1 receptor agonist-induced weight loss.

Minas Nalbandian, Jameel Lone, Emmeran Le Moal, Ireh Kim, Kaitlin Jeuris, Yutong Kelly Li, Peggy Kraft, Meng Zhao, Kassie Koleckar, Zeyuan Zhang, Katrin J Svensson, Helen M Blau.

  Glucagon-like peptide-1 receptor agonists, including long-acting semaglutide, are transformative anti-obesity therapies. However, emerging evidence indicates that weight loss may come at the expense of skeletal muscle mass, a tissue essential for mobility, metabolic regulation, and overall health. Here, we show that inhibition of the gerozyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme that increases with injury and aging, improves muscle repair and strength recovery in the presence of semaglutide. In a high fat diet-induced mouse model of obesity, semaglutide alone caused significant loss of muscle mass, while preserving contractile function. Following injury, obese mice exhibited pathological calcifications previously reported for the heritable myopathy, Duchenne Muscular Dystrophy. Semaglutide had both beneficial and deleterious effects, reducing calcific remodeling, but causing reduced regenerated myofiber sizes. This impaired regenerative myofiber growth in semaglutide-treated mice was surmounted by cotreatment with a 15-PGDH inhibitor (PGDHi), which stimulated muscle stem cell function and myofiber growth, leading to enhanced strength. Importantly, PGDHi synergizes with semaglutide to boost postinjury muscle quality and muscle force without compromising weight loss.

Keywords:  15-PGDH (gerozyme); GLP-1 receptor agonist; muscle stem cells; semaglutide; skeletal muscle regeneration

DOI:  https://doi.org/10.1073/pnas.2606533123
bioRxiv. 2026 May 20. pii: 2026.05.18.725925. [Epub ahead of print]

Myogenic dysregulation underlies tongue overgrowth in Beckwith-Wiedemann syndrome.

Elisia D Tichy, Anna T Nguyen, Mariah A Byrne, Rose D Pradieu, Gavriela Kalish-Schur, Mara Fallon, Snehal Nirgude, Darryl Kinnear, Harry P Kozakewich, Jennifer M Kalish.

Macroglossia is a clinically significant feature of Beckwith-Wiedemann syndrome (BWS), but the cellular basis of tongue overgrowth remains poorly defined. Here, using pediatric tongue specimens from molecularly defined BWS subtypes and age-matched nonBWS controls, we show that BWS macroglossia is characterized by skeletal muscle fiber hypertrophy rather than increased fiber number. This phenotype is not explained by expansion or increased proliferation of satellite cells in situ , and prospectively isolated tongue satellite cells do not exhibit enhanced proliferation under growth conditions in vitro . Instead, BWS progenitors adopt distinct differentiation-associated regulatory states. IC2 loss of methylation cells sustain proliferative activity during differentiation and form enlarged myotubes, consistent with a cell-autonomous hypertrophic program. In contrast, pUPD11 cells display activation of NOTCH signaling and progenitor-associated programs, together with attenuated progression toward terminal myogenic differentiation. These findings identify skeletal muscle hypertrophy as a core tissue-level feature of BWS macroglossia and reveal that epigenetically defined BWS subtypes engage divergent myogenic programs that converge on a shared hypertrophic tissue phenotype. Together, these data define subtype-specific myogenic states in a rare human disease tissue and provide a framework for understanding how distinct epigenetic changes can produce a common overgrowth phenotype.
Highlights: BWS macroglossia is associated with skeletal muscle fiber hypertrophy, not fiber hyperplasia Tongue satellite cell abundance and proliferation are not increased in situ in BWS IC2 loss of methylation cells sustain proliferation during differentiation and form enlarged myotubespUPD11 cells show enhanced NOTCH signaling and a constrained myogenic state.
In brief: Tichy et al. show that Beckwith-Wiedemann syndrome macroglossia is driven by skeletal muscle hypertrophy and that distinct BWS molecular subtypes engage different myogenic regulatory programs. IC2 loss of methylation cells sustain proliferation during differentiation, whereas pUPD11 cells exhibit NOTCH-associated restraint of myogenic progression.

DOI: https://doi.org/10.64898/2026.05.18.725925
bioRxiv. 2026 May 26. pii: 2026.05.22.727267. [Epub ahead of print]

Loss of ACTA1 leads to delayed γ-AChR / ε-AChR switch in skeletal muscle in mice.

Yun Liu, Qiaohong Ye, Weichun Lin.

Skeletal muscle actin forms the core structural component of thin filaments, which interact with thick filaments to generate contractile force. In addition to force production, the character of muscle contraction activity itself is thought to provide mechanical cues that influence synaptic development and maturation. In mouse skeletal muscle there is an early post-natal switch from embryonic forms of actin to the adult isoform, ACTA1, which increases both filament stability and force production. Newborn mice deficient for ACTA1 ( Acta1 -/- ), although initially able to breath, move and suckle, develop profound muscle weakness and die during the early neonatal period, despite a compensatory, increase in expression of embryonic actins. We took advantage of this to better understand the response of the neuromuscular junction (NMJ) to a disruption in contractility and activity-dependent signaling during development. Morphological analyses of the diaphragm in Acta1 -/- mice revealed that the patterning and formation of the NMJ proceed normally through postnatal day 5 (P5), the day at which pups begin to die. Short-term synaptic plasticity, assessed as the endplate potential (EPP) response to paired-pulse stimulation, was also unchanged, indicating normal presynaptic release of neurotransmitters. In contrast, electrophysiological recordings demonstrated significantly prolonged rise and decay kinetics of miniature and evoked endplate potentials, indicating altered postsynaptic receptor properties. Consistent with these functional changes, quantitative real-time PCR showed a reduced ratio of ε- to γ-acetylcholine receptor (AChR) subunit mRNA, reflecting a delay in the developmental switch from embryonic γ-containing to adult ε-containing AChRs. Together, these findings indicate that α-skeletal actin is dispensable for early NMJ morphogenesis but is required for timely postsynaptic receptor maturation, demonstrating a critical role for muscle contractile activity in coordinating synaptic development at the NMJ.
Highlights: Skeletal muscle α-actin (ACTA1) is the principal structural component of thin filaments and a key determinant of contractile activity. Using Acta1 -/- mice, we show that NMJ patterning and early morphogenesis occur normally despite severe impairment in muscle contractility. Electrophysiological analysis of the NMJ shows that presynaptic function remains intact, as evidenced by normal paired-pulse responses. In contrast, postsynaptic maturation is disrupted, with prolonged endplate potential kinetics indicating altered AChR function.This defect is associated with a delayed γ- to ε-AChR subunit switch, a key step in postnatal NMJ maturation. These findings identify ACTA1-dependent contractile activity plays a critical role in timely postsynaptic receptor maturation.

DOI: https://doi.org/10.64898/2026.05.22.727267
Mech Ageing Dev. 2026 Jun 01. pii: S0047-6374(26)00057-6. [Epub ahead of print]232 112205

The epigenetic control of inflammaging in skeletal muscle and adipose tissue.

Diego Gomes de Melo, Vivian Cristina da Cruz Rodrigues, Gustavo José de Sá Pereira, Célio Junior da Costa Fernandes, Leandro Pereira de Moura.

  Metabolic inflexibility, mitochondrial dysfunction, and persistent low-grade inflammation are recognized as fundamental hallmarks of biological ageing and key drivers of the inflammaging process. Ageing is associated with a progressive decline in cellular function and systemic homeostasis, particularly affecting skeletal muscle and white adipose tissue, which are central to energy metabolism and inflammatory regulation. In skeletal muscle, ageing leads to reduced oxidative capacity, impaired mitochondrial turnover, and anabolic resistance. In adipose tissue, adipocytes exhibit hypertrophy, hypoxia, and increased immune cell infiltration. Together, these changes promote persistent activation of inflammatory pathways and contribute to systemic insulin resistance. Epigenetic regulation plays a key role in linking metabolic stress to gene expression, modulating mechanisms such as DNA methylation, histone acetylation, and hydroxymethylation, thereby influencing chromatin accessibility in genes involved in ageing. Importantly, lifestyle interventions, including caloric restriction and physical exercise, can partially reverse these effects by reprogramming the epigenome. Both aerobic and resistance exercise promote epigenetic modifications associated with improved mitochondrial function, enhanced myogenesis, better adipocyte health, and reduced inflammatory gene expression. Thus, inflammaging is a dynamic and modifiable process, in which epigenetic plasticity connects metabolic dysfunction to chronic inflammation while also enabling interventions that preserve metabolic health during ageing.

Keywords:  Ageing; Epigenetics; Exercise; Inflammaging; Insulin Resistance; Nutrition

DOI:  https://doi.org/10.1016/j.mad.2026.112205
Cell Death Dis. 2026 Jun 03.

PEBP4 alleviates muscle wasting in lung cancer cachexia via KEAP1-NRF2-mediated redox homeostasis.

Yaru Xia, Yuqi Han, Weiquan Li, Tiexi Yu, Diaoyi Tan, Daojia Miao, Wen Li, Jiaming Wu, Qianqian Luo, Jiemin Li, Pian Liu, Hongli Liu, Guixiao Huang, Xiaoping Zhang, Hongmei Yang.

Cancer-associated cachexia (CAC) is a multifactorial metabolic syndrome characterized by progressive skeletal muscle wasting. However, the molecular link between tumor metabolic stress and muscle degradation remains elusive. Here, we identify phosphatidylethanolamine-binding protein 4 (PEBP4) as a key regulator of muscle homeostasis under cachectic conditions. PEBP4 expression is markedly suppressed in lung cachectic models and is inversely correlated with tumor-derived lactate levels. Mechanistically, PEBP4 stabilizes NRF2 by competitively binding to KEAP1, enhancing antioxidant defense, inhibiting NF-κB signaling, and downregulating muscle atrophy-related genes MuRF1 and Fbxo32 (also known as Atrogin-1). In vitro and in vivo overexpression of PEBP4 mitigates oxidative stress, preserves muscle mass, and improves strength and endurance in Lewis lung carcinoma tumor-bearing mice. These protective effects are significantly attenuated by NRF2 inhibition, highlighting its critical role in PEBP4-mediated signaling. Collectively, our findings uncover a tumor lactate-PEBP4-NRF2 axis linking cancer metabolism to redox imbalance and muscle wasting, and suggest the therapeutic potential of targeting the PEBP4-NRF2 pathway in lung cancer-associated cachexia.

DOI: https://doi.org/10.1038/s41419-026-08925-5
Curr Protoc. 2026 Jun;6(6): e70393

Measuring Calcium Efflux in Isolated Primary Mitochondria.

Ta'Aliyah M Jones, Stephen Hurst, Michael J Bround.

  Mitochondrial calcium (mCa2+) homeostasis promotes oxidative metabolism within the physiological range; however, dysregulation can trigger necrotic cell death in diseases such as cardiac ischemia-reperfusion injury, muscular dystrophy, and neurodegenerative disorders, including Alzheimer's disease. It is widely understood that mitochondria exhibit rapid Ca2+ uptake primarily mediated by the mitochondrial calcium uniporter (MCU) complex, and that Ca2+ is exported via a combination of Na+/Ca2+ and H+/Ca2+ exchange processes. However, the proteins which mediate mCa2+ transport have only been partially identified. A particular challenge in determining which proteins mediate mCa2+ efflux and their relative contributions to mCa2+ homeostasis is the lack of a clear, reproducible assay for mCa2+ efflux applicable across genotypes. Here, we provide instructions for an optimized fluorometric method to measure mCa2+ efflux in isolated mitochondria that establishes robust Ca2+ efflux signals, differentiates between total and Na+-independent Ca2+ efflux modalities, and generates highly reproducible data, allowing comparisons across tissues and genotypes. © 2026 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Total Calcium Efflux Assay in Isolated Mitochondria Alternate Protocol 1: Na+-Independent Calcium Efflux Assay in Isolated Mitochondria Support Protocol 1: Isolation of Cardiac Mitochondria Support Protocol 2: Isolation of Skeletal Muscle Mitochondria Support Protocol 3: Isolation of Liver Mitochondria Support Protocol 4: Isolation of Cell Line Mitochondria Basic Protocol 2: Analysis of Calcium Efflux.

Keywords:  calcium signaling; fluorimetry; mitochondria; mitochondrial calcium

DOI:  https://doi.org/10.1002/cpz1.70393
Int Immunopharmacol. 2026 Jun 05. pii: S1567-5769(26)00813-1. [Epub ahead of print]185 116967

CILP2 exacerbates diabetes-induced muscle atrophy by over-activating skeletal muscle autophagy and inflammation via the P38 MAPK pathway.

Lun Dong, Siqi Chen, Lingling Hu, Yingying Shan, Yitao Xia, Zhili Chen, Jiaxin Liu, Dongfang Liu, Gangyi Yang, Mengliu Yang, Ke Li.

   BACKGROUND: Muscle atrophy seriously affects the prognosis of people with diabetes, yet effective interventions remain limited. Although CILP2 is upregulated in skeletal muscle and associated with type 2 diabetes, its potential role in diabetes-induced muscle atrophy remains unknown.
METHODS: A diabetic model was constructed by feeding a high-fat diet combined with intraperitoneal injection of streptozotocin. The regulatory role and mechanism of CILP2 in diabetic muscle atrophy were studied in wild-type mice, CILP2-KO mice, and mice with muscle-specific injection of Ad-GFP or Ad-CILP2. The assessment of muscle atrophy indicators was conducted through the utilization of immunofluorescence, western blotting, and electron microscopy.
RESULTS: CILP2 expression was markedly elevated in the gastrocnemius muscles of ob/ob and db/db mice (all P < 0.01). CILP2 knockdown mitigated diabetes-induced muscle mass loss and dysfunction (P < 0.05), while increasing the muscle fiber CSA (P < 0.05). And the expressions of Atrogin1, MuRF1, LC3II/LC3I and P62 in muscle reduced (all P < 0.05), with an improvement of the autophagy inhibition. Nevertheless, CILP2 overexpression in the gastrocnemius of diabetic mice resulted in a further exacerbation of muscle atrophy, accompanied by a more pronounced autophagy activation (all P < 0.05). CILP2 overexpression exacerbated mature myotubes atrophy induced by palmitic acid, accompanied by increased expressions of Atrogin1, MuRF1 and LC3II/LC3I, and decreased expression of P62 and myotube diameter (all P < 0.05). By inhibiting autophagy, chloroquine mitigated the CILP2 overexpression-induced increase in Atrogin1 expression and reduction in myotube diameter (all P < 0.05). Mechanistically, CILP2 overexpression activated the P38 MAPK pathway in diabetic mice and PA-treated myotubes, consequently triggering the release of IL-1β, IL-6, and TNF-α (all P < 0.05). The P38 inhibitor SB202190 suppressed this cascade, thereby mitigating autophagy overactivation and preventing myotube atrophy (all P < 0.05).
CONCLUSIONS: CILP2 upregulation exacerbated the diabetes-induced muscle atrophy by activating autophagy and inflammation through the P38 MAPK pathway, thereby proposing its inhibition as a promising therapeutic strategy.

Keywords:  Autophagy; CILP2; Diabetes; Muscle atrophy; p38 MAPK

DOI:  https://doi.org/10.1016/j.intimp.2026.116967
medRxiv. 2026 May 20. pii: 2026.05.11.26351978. [Epub ahead of print]

Single-fiber morphometry and spatial transcriptomics reveal selective oxidative muscle fiber atrophy in non-metastatic breast cancer.

Alan D Mizener, Stuart A Clayton, Alexa L Bostic, Isabelle A Oberhauser, Hannah E Wilson, Marcella A Whetsell, Hannah Hazard-Jenkins, Jessica F Partin, Emidio E Pistilli.

Cancer-related fatigue is the most common and persistent symptom in breast cancer, with fatigue reported up to 10 years post-diagnosis. Unlike many cancers, fatigue in breast cancer often arises during early-stage disease in the absence of cachexia. While many factors contribute to fatigue, the direct contribution of cancer-associated skeletal muscle pathology remains poorly understood. Here we analyzed pectoralis major muscle biopsies from individuals with non-metastatic breast cancer and non-cancer controls using single-fiber morphometry and spatial transcriptomics. We identified fiber-type-specific structural alterations and spatially localized transcriptional reprogramming within the muscle microenvironment. Single-fiber morphometry revealed selective atrophy of oxidative type I and type IIa muscle fibers, while glycolytic type IIx fibers were relatively preserved. Concordant spatial transcriptomic profiling revealed suppression of oxidative metabolic programs, evidence of mitochondrial dysfunction, and spatially localized catabolic signaling originating from intramuscular adipocytes. This study introduces an integrated framework for profiling skeletal muscle architecture and spatially localized gene expression in surgically obtained muscle biopsies and represents the first application of spatial transcriptomics to human skeletal muscle from individuals with cancer. These findings demonstrate structural and metabolic remodeling of skeletal muscle in non-metastatic breast cancer and suggest targeting muscle metabolism represents a promising therapeutic strategy for cancer-related fatigue.

DOI: https://doi.org/10.64898/2026.05.11.26351978
bioRxiv. 2026 May 20. pii: 2026.05.18.725456. [Epub ahead of print]

Mechanical Loading Induces the Radial Growth of Myofibrils and Myofibrillogenesis via an mTORC1-Dependent Mechanism.

Corey Gk Flynn, Ramy K A Sayed, Anthony N Lange, Wenyuan G Zhu, Troy A Hornberger.

Increased mechanical loading induces skeletal muscle growth and, at the ultrastructural level, promotes myofibrillogenesis and the radial growth of myofibrils. However, the mechanisms regulating these ultrastructural adaptations are not known. Here, we sought to determine whether the mechanistic target of rapamycin complex 1 (mTORC1) regulates these processes. To accomplish this, muscle-specific, tamoxifen-inducible raptor knockout (iRAmKO) mice were used to inhibit signaling through mTORC1, and growth was induced with a model of chronic mechanical overload (MOV). Using a next-generation fluorescence imaging pipeline for ultrastructural analyses, we found that mTORC1 is a critical regulator of the myofibrillogenesis and radial growth of myofibrils that occur in response to MOV. Together with other recent advances in the field, we propose a model in which mTORC1 acts as a gatekeeper that permits the retention, rather than the synthesis, of proteins that drive the ultrastructural adaptations.

DOI: https://doi.org/10.64898/2026.05.18.725456
bioRxiv. 2026 May 27. pii: 2026.02.22.707291. [Epub ahead of print]

Stress unmasks impaired endocrine coordination of glucose metabolism in dystrophin deficiency.

Gretel S Major, Cara A Timpani, Hannah Lalunio, Jiayi Chen, Lauren Boatner, Nicholas Giourmas, Stephanie Kourakis, Eva van den Berg, Ekaterina Salimova, Joel Eliades, Gang Zheng, Rong Xu, Sukhvir Kaur Bhangu, Thirimadura V H Mendis, Joel R Steele, Ralf B Schittenhelm, Deirdre L Merry, Louise Lantier, Christoph E Hagemeyer, Francesca Cavalieri, Karen Caeyenberghs, Aaron P Russell, Michael de Veer, Craig A Goodman, Alan Hayes, Emma Rybalka, Charles P Najt, Angus Lindsay.

Skeletal muscle orchestrates systemic metabolism, dynamically coordinating glucose uptake and fuel use to match energy demand. In Duchenne muscular dystrophy, loss of dystrophin is associated with altered metabolic regulation. In the mdx mouse, we show that physiological stress reveals impaired coordination between insulin and stress responses: glucocorticoid signalling increases without a proportional rise in insulin secretion, resulting in systemic hyperglycaemia despite preserved capacity for muscle glucose uptake. These data support a multi-tissue dystrophinopathy associated with altered endocrine-metabolic coordination. Skeletal muscle glycogen is elevated and incompletely mobilised under stress. The heart maintains high glucose uptake, whereas the brain exhibits reduced uptake, highlighting tissue specific differences in metabolic response. Acute insulin supplementation improves systemic glucose control and restores stress-induced behavioural deficits. Likewise, empagliflozin-mediated glucose offloading reduces stress-associated blood glucose spikes and is associated with improved muscle function to levels comparable with standard care prednisolone. These findings identify impaired coordination of endocrine and metabolic responses during stress as a contributor to metabolic vulnerability in DMD and suggest that modulating insulin availability or glucose flux can improve systemic metabolic control.

DOI: https://doi.org/10.64898/2026.02.22.707291
Am J Physiol Cell Physiol. 2026 Jun 04.

The Extracellular Matrix as a Central Regulator of Aging and Tissue Adaptation to Exercise.

Ching-Yan Chloé Yeung, Alexander Nyström.



Keywords:  Collagen; injury; proteoglycan; sport

DOI:  https://doi.org/10.1152/ajpcell.00303.2026
Proc Natl Acad Sci U S A. 2026 Jun 09. 123(23): e2504146123

Positive allosteric modulator selective for adult muscle nicotinic acetylcholine receptor.

Richard G Webster, Setareh Alabaf, Anna Li, Rene Beerli, Sandra Siehler, Pierre-Eloi Imbert, Leonard Lee, Judith Cossins, Magdalena Koziczak-Holbro, Ludivine Flotte, Laurent Gaudet, Nicole Gerwin, David Beeson, Yin Y Dong.

  The muscle nicotinic acetylcholine receptor (AChR) is the key mediator of neuromuscular signal transmission and is essential for all voluntary movement in our body. In this study, we present DC-98-LC74, a positive allosteric modulator (PAM) for the adult skeletal muscle-type AChR. Through using Ca2+ fluorometric imaging plate reader (FLIPR) assays, we demonstrate that it is selective for the adult skeletal muscle AChR over neuronal subtypes. Neurophysiological recordings from ex vivo mouse diaphragm preparations revealed that DC-98-LC74 elongates the endplate currents of wildtype (WT) adult but not fetal channel containing diaphragms. Single channel studies on chimeric channels of the adult and fetal receptor, and in saturating concentrations of choline, suggest that the PAM does not bind at either orthosteric site, but works by increasing the unliganded open probability via a mechanism that involves the ε M2-M3 loop. We also show that DC-98-LC74 increases the burst duration of multiple fast channel mutant AChR to WT levels, suggesting that positive allosteric modulation could be a therapeutic strategy for this difficult to treat subtype of congenital myasthenia. Promising preliminary data on aged sarcopenic mice also demonstrate that positive allosteric modulation of the muscle type AChR has potential benefits not only in myasthenia but also other neuromuscular disorders involving the neuromuscular junction.

Keywords:  acetylcholine receptor; allosteric modulator; myasthenia; sarcopenia

DOI:  https://doi.org/10.1073/pnas.2504146123
J Physiol. 2026 Jun 02.

Neither intracellular oxygen availability nor mitochondrial coupling explain lower oxidative capacity in older human vastus lateralis muscle in vivo.

Luke R Arieta, Zoe H Smith, Rajakumar Nagarajan, Martin Meyerspeer, Jane A Kent.

  Skeletal muscle oxidative capacity is a useful in vivo marker of mitochondrial health and is generally lower in the knee-extensor muscles of older compared with younger adults. The causes of this lower oxidative capacity in older muscle are unclear. We used magnetic resonance spectroscopy to investigate the influence of intramyocellular oxygen availability and the coupling (P/O ratio) between mitochondrial respiration and ATP production on oxidative capacity in the knee-extensor muscles of 14 young and 10 older adults. Participants completed a 24-s contraction protocol followed by 10 min of recovery and 8 min of cuff occlusion while interleaved 31P and 1H spectroscopy data were acquired. Oxidative capacity was calculated as the rate constant of phosphocreatine recovery, and intramyocellular oxygen tension ( PO2${{P}_{{{{\mathrm{O}}}_2}}}$ ) was determined from the deoxymyoglobin signal. Critical PO2${{P}_{{{{\mathrm{O}}}_2}}}$ , the point at which respiration is limited owing to insufficient oxygen availability, and the P/O ratio were determined for each individual. Oxidative capacity was lower in older than younger muscles, whereas neither critical PO2${{P}_{{{{\mathrm{O}}}_2}}}$ nor the P/O ratio differed between groups. On average, PO2${{P}_{{{{\mathrm{O}}}_2}}}$ remained above the critical PO2${{P}_{{{{\mathrm{O}}}_2}}}$ throughout the protocol in both young and older muscle. Oxidative capacity was modestly related to PO2${{P}_{{{{\mathrm{O}}}_2}}}$ during recovery in young but not older muscle, and mitochondrial coupling was unrelated to oxidative capacity. These novel results do not support a primary role for limited oxygen availability or impaired mitochondrial coupling in the lower oxidative capacity of older knee-extensor muscles and suggest instead that other mechanisms, such as lower mitochondrial content, might be responsible. KEY POINTS: Knee-extensor muscle oxidative capacity is generally lower in older age, but the questions of whether this decline is attributable, in part, to insufficient oxygen availability or altered coupling between mitochondrial energy production and oxygen consumption remain open. Interleaved 31P and 1H magnetic resonance spectroscopy was used to measure intramyocellular phosphocreatine and deoxygenated myoglobin in vivo, respectively, in the knee-extensor muscles of young and older adults in response to a 24-s contraction protocol and 8 min of circulatory occlusion. Oxidative capacity was indeed lower in the older muscles, but intracellular oxygen availability during and after contractions was sufficient to support oxidative metabolism and did not differ in young and older muscles. Mitochondrial coupling did not differ by age and was unrelated to oxidative capacity. Thus, the lower knee-extensor muscle oxidative capacity in older age is not a result of inadequate intramyocellular oxygen availability or differences in mitochondrial coupling.

Keywords:  ATP; P/O ratio; ageing; cellular respiration; deoxymyoglobin; intracellular oxygen tension; knee extensors; phosphocreatine recovery

DOI:  https://doi.org/10.1113/JP291176
Physiol Rep. 2026 Jun;14(11): e70962

Aerobic exercise partially improves the skeletal muscle phenotype in a model of heart failure with preserved ejection fraction in male mice.

Cielo Martínez Martínez, Jorge Fragoso Medina, Estefanía Bravo Sánchez, Bianca Nieblas, Alfredo Saavedra Molina, Christian Cortés Rojo, Salvador Manzo Ávalos, Noemí García, Rocío Montoya Pérez.

  Heart failure with preserved ejection fraction (HFpEF) is associated with skeletal muscle dysfunction that contributes to exercise intolerance and disease progression. Altered Ca2+ homeostasis and increased oxidative stress have been proposed as mechanisms underlying muscle weakness in HFpEF; however, the effects of aerobic exercise on skeletal muscle physiology in this condition remain unclear. This study evaluated the impact of moderate-intensity aerobic exercise on skeletal muscle contractile function, fatigue resistance, oxidative stress, and mRNA expression of key Ca2+-handling proteins in a model with features consistent with HFpEF. Male C57BL/6J mice were assigned to Control, Exercise, HFpEF (HFD + L-NAME-treated), and HFpEF+Exercise groups. HFpEF-like features were induced by an 8-week high-fat diet combined with L-NAME administration. During the final 4 weeks, mice underwent aerobic exercise training. Soleus muscles were analyzed using in vitro contractile recordings, oxidative stress markers, and RT-qPCR for RyR1, SERCA1, and NCX3 mRNA expression. HFpEF (HFD + L-NAME-treated mice) showed reduced contractile force and fatigue resistance, increased oxidative stress, and decreased SERCA1 and NCX3 expression. Aerobic exercise partially restored muscle performance and improved redox balance without normalizing Ca2+-handling gene expression. These findings suggest that aerobic exercise enhances skeletal muscle function in HFpEF-like models, primarily by modulating redox homeostasis.

Keywords:  calcium; cardiovascular disease; muscle fatigue; oxidative stress; physical activity; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.70962
Mol Biol Rep. 2026 Jun 03. pii: 880. [Epub ahead of print]53(1):

A systematic review of molecular signaling in the muscle-brain-gut axis: exercise-induced myokines and microbial metabolites as key mediators.

Rastegar Hoseini, Zahra Hoseini, Behzad Heydarpour, Mahtab Faraji.

  Exercise physiology is evolving from an organ-based framework toward a systems-level understanding, where molecular interactions between muscle, brain, and the gut microbiome critically influence performance and health. This review systematically examines the genetic, molecular, and cellular bases of this triad, with a focus on translational insights for disease prevention and human optimization. A systematic search of PubMed, Embase, and Web of Science was conducted up to October 2023 to identify studies exploring molecular pathways linking skeletal muscle, cognitive/affective function, and gut microbiota in exercise contexts. Inclusion criteria were original research articles investigating at least two components of the muscle-brain-gut axis. Exclusion criteria included non-English articles, conference abstracts, and studies without molecular data. The PRISMA 2020 guidelines were followed. The search strategy is detailed in Supplementary Material. Evidence was categorized into Grades 1 through 4 based on methodological rigor, omics integration, reproducibility, and translational relevance to human physiology and disease models. Analysis included 154 studies encompassing 987 molecular associations. Among these, 59 associations (Grades 1-2) provided robust evidence for genetically and functionally validated pathways, including myokine-mediated (e.g., irisin, BDNF) and microbially derived metabolites (e.g., SCFAs, tryptophan derivatives) that modulate neuroplasticity, mitochondrial function, inflammation, and HPA axis activity. Psychobiological factors influenced microbial composition, illustrating bidirectional gut-brain-muscle signaling. Most associations (n = 952) were limited by methodological variability or insufficient mechanistic depth. The integration of multi-omics platforms (metagenomics, metabolomics, proteomics) emerges as a key tool for personalized exercise interventions and biomarker discovery. This review synthesizes molecular evidence for the muscle-gut-brain axis as an integrative determinant of exercise responsiveness and disease resilience. We highlight genetic and metabolic pathways with diagnostic and therapeutic potential, aligning with the development of molecular tools for precision medicine. Future interdisciplinary research should leverage artificial intelligence and longitudinal omics to translate these mechanisms into targeted strategies for performance enhancement and disease prevention.

Keywords:  Gut–brain axis; Microbial metabolites; Mitochondrial biogenesis; Molecular exercise physiology; Myokines; Neuroplasticity; Omics; Precision health; Translational medicine

DOI:  https://doi.org/10.1007/s11033-026-12035-y
J Appl Physiol (1985). 2026 Jun 04.

Limited reproducibility of individual physiological adaptations to repeated endurance exercise training.

Ingvill Urianstad Odden, Håvard Hamarsland, Tomas Urianstad Odden, Daniel Hammarström, Anne Mette Rustaden, Lise Koll, Marita Hanestadhaugen, Steen Larsen, Stian Ellefsen, Joar Hansen, Håvard Nygaard, Carsten Lundby, Knut Sindre Mølmen.

  Between-individual variability in physiological adaptations to endurance exercise training is often interpreted as reflecting stable differences in training responsiveness. However, whether the capacity for physiological adaptation itself represents a stable, individual-specific trait under repeated exposure to the same training stimulus remains unclear. This study investigated the reproducibility of within-individual adaptations to repeated endurance training. Forty-two middle-aged, untrained men and women completed two similar eight-week endurance training periods (TP1 and TP2), separated by an eight-week detraining period. Assessments spanned multiple physiological and performance outcomes, including hemoglobin mass (Hbmass), skeletal muscle citrate synthase (CS) activity, capillaries∙fibre-1, maximal oxygen uptake (V̇O2max), and 15-minute maximal mean power output (MMPO15-min). Within-individual reproducibility was evaluated using intraclass correlation coefficients with [95% confidence intervals]. Participants completed 23.9 (0.4) and 23.8 (0.7) training sessions in TP1 and TP2, with minimal within-individual variation. Baseline values were highly consistent between periods for V̇O2max (0.98 [0.97, 0.99]), MMPO15-min (0.96 [0.93, 0.97]), and most other outcomes, indicating effective detraining. Nevertheless, reproducibility of within-individual adaptations was poor for Hbmasssub> (0.00 [0.00, 0.30]), CS activity (0.15 [0.00, 0.33]), capillaries∙fibre-1 (0.00 [0.00, 0.36]), V̇O2max (0.19 [0.00, 0.37]), and MMPO15-min (0.20 [0.00, 0.37]). Within-individual variability in hematological and skeletal muscle adaptations accounted for little of the within-individual variability in V̇O2max and MMPO15-min responses. This study demonstrates that individual adaptations to endurance training exhibit limited reproducibility across multiple physiological and performance outcomes. These findings indicate that physiological adaptability to endurance training does not reflect a stable, individual-specific attribute, but instead emerge from dynamic and context-dependent biological processes.

Keywords:  endurance training; individual training response; intraindividual variability; personalized training prescriptions; training response variability

DOI:  https://doi.org/10.1152/japplphysiol.00154.2026
J Physiol. 2026 Jun 02.

A transcription-driven model of scaled myonuclear accretion reveals a quantitative role for nuclear reserve capacity.

Kenth-Arne Hansson.



Keywords:  cell volume; scaling; skeletal muscle fibre; syncytium

DOI:  https://doi.org/10.1113/JP291492
Nat Commun. 2026 Jun 05.

AMC-F1 regulates mitochondria-autophagy crosstalk independent of nutrient stress.

Yuqin Wang, Raksha K Rao, Trung Vu, Ayano Sekine, Zhengmei Mao, Nami McCarty.

Mitochondria and autophagy are fundamental yet distinct regulators of cellular homeostasis. Here, we identify AMC-F1 (Autophagy-Mitochondria Coupling Factor 1; formerly TRIM44) as a central integrator of mitochondrial bioenergetics and autophagy. Using Amcf1 knockout and knock-in mouse models, we demonstrate that AMC-F1 bidirectionally regulates these pathways: its loss reduces mitochondrial respiration and autophagic flux, whereas its overexpression promotes mitochondrial elongation and increases autophagy independently of nutrient stress. Transcriptomic analyses reveal AMC-F1-dependent regulation of mitochondrial biogenesis programs that engage autophagy, involving mitochondrial respiratory chain complex genes under basal conditions and mitochondrial organization factors under starvation-induced autophagy. Although dispensable under homeostasis, this coupling becomes essential during stress adaptation. In an acute liver-injury model, Amcf1 knock-in mice were fully protected, exhibiting elevated OPA1, reduced caspase-3 and PARP activation, and preserved Beclin 1. This functional duality reflects AMC-F1's ability to modulate the mitochondrial integrated stress response (mtISR), enabling adaptive ATF4 signaling while preventing maladaptive responses when stress exceeds a threshold. Autophagy upregulation by AMC-F1 is critical for fine-tuning the ISR and preserving cellular resilience. Together, our findings position AMC-F1 as a stress-responsive gatekeeper and a novel coordinator of mitochondrial-autophagy crosstalk, defining a cellular state primed for stress adaptation.

DOI: https://doi.org/10.1038/s41467-026-73841-3
Aust J Gen Pract. 2026 Jun;55(6): 369-372

Muscle matters: A proposed algorithm to guide screening, assessment and management of poor muscle health in primary care.

Robin M Daly, Linda Govan, David Scott, Simon Willcock, Anita Muñoz, Anthony Villani.

BACKGROUND: Muscle health can decline from the third decade of life, potentially leading to the disease sarcopenia, which is characterised by low skeletal muscle mass, strength, and/ or impaired physical function. Sarcopenia is a serious condition associated with many chronic conditions and increased healthcare costs, emphasising the need for early detection and intervention. However, in routine clinical practice, muscle health remains poorly recognised, underappreciated and rarely considered.
OBJECTIVE: To develop a proposed clinical muscle health monitoring and management algorithm for use by healthcare professionals in identifying patients with or at-risk for poor muscle health to support early detection and timely management.
DISCUSSION: Primary care represents an ideal setting to identify and support patients with or at-risk for poor muscle health. This article outlines an easy-to-use and practical four- step muscle health algorithm (Suspect, Ask and/or Assess, Prevent or Manage, REVIEW) for early identification of poor muscle health, allowing for timely prevention or intervention.

DOI: https://doi.org/10.31128/AJGP-06-25-7703
EMBO Mol Med. 2026 Jun 03.

Microbiota dysbiosis influences immune system and muscle pathophysiology of dystrophin deficient mice.

Andrea Farini, Luana Tripodi, Chiara Villa, Francesco Strati, Amanda Facoetti, Guido Baselli, Jacopo Troisi, Annamaria Landolfi, Caterina Lonati, Davide Molinaro, Michelle Wintzinger, Stefano Gatti, Barbara Cassani, Flavio Caprioli, Federica Facciotti, Mattia Quattrocelli, Yvan Torrente.

Duchenne muscular dystrophy (DMD) is a progressive, severe muscle-wasting disease caused by mutations in DMD, encoding dystrophin, that leads to loss of muscle function with cardiac/respiratory failure and premature death. Since dystrophic muscles are sensed by infiltrating inflammatory cells, and gut microbial communities can cause immune dysregulation and metabolic syndrome, we sought to investigate whether intestinal bacteria support the muscle immune response in the mdx dystrophic murine model. We highlighted a strong correlation between DMD disease features and the relative abundance of Prevotella. Furthermore, the absence of gut microbes through the generation of mdx germ-free animal model, as well as modulation of the microbial community structure by antibiotic treatment, influenced muscle immunity and fibrosis. Intestinal colonization of mdx mice with eubiotic microbiota was sufficient to reduce inflammation and improve muscle pathology and function. This work identifies a potential role for the gut microbiota in the pathogenesis of DMD.

DOI: https://doi.org/10.1038/s44321-026-00445-1
J Aging Phys Act. 2026 May 29. 1-8

Association of Physical Activity With Changes in Skeletal Muscle Mass in Patients With Acute Stroke.

Kenji Yamaki, Koutatsu Nagai, Masashi Kanai, Keishi Yoshida, Kaoru Sakuma, Yumi Aga, Shuta Uchida, Atsushi Keyaki.

  Reduced skeletal muscle mass in patients with stroke is associated with poor clinical outcomes. Although physical activity helps mitigate this loss, the relationship between physical activity and changes in skeletal muscle mass remains unclear. This study examined the association between changes in skeletal muscle mass and physical activity in patients with acute stroke, including those with moderate-to-severe stroke. This retrospective cohort study evaluated 167 patients who were consecutively admitted within 48 hr of stroke onset between December 2022 and March 2024 based on data extracted from hospital medical records. The dependent variable was the change in skeletal muscle mass (in kilograms), and the independent variables were light- (LPA) and moderate- to vigorous-intensity physical activity (in minutes per day) and the National Institutes of Health Stroke Scale score. Associations were examined using multiple regression analysis. There was a significant loss of skeletal muscle mass during hospitalization (mean change: -1.5 kg [SD: 1.6], p < .001). Of the 167 patients, 120 were in the mild stroke group and 47 in the moderate-to-severe group. LPA was significantly associated with reduced skeletal muscle mass loss in the mild stroke group (B = 0.004, 95% confidence interval [0.001, 0.007], p = .009, adjusted R2 = .24). No significant association was detected in the moderate-to-severe group. Patients with acute stroke experienced significant skeletal muscle mass loss during hospitalization. LPA was independently associated with less skeletal muscle mass loss in the mild stroke group. The findings suggest that increasing LPA may help prevent skeletal muscle mass loss in patients with mild acute stroke.

Keywords:  light-intensity physical activity; sarcopenia; stroke severity

DOI:  https://doi.org/10.1123/japa.2025-0139
Eur J Appl Physiol. 2026 Jun 06.

Effects of tyrosine kinase inhibitors on skeletal muscle metabolism: a link with muscle complaints.

Lando Janssen, Charlotte A Hoogstraten, Neeltje A E Allard, Tom J J Schirris, Maria T E Hopman, Nicole M A Blijlevens, Silvie Timmers.

  Chronic myeloid leukemia (CML) patients receiving tyrosine kinase inhibitors (TKIs) often report muscle complaints (MC). Strategies to prevent or attenuate these muscle complaints remain enigmatic as the underlying mechanism is unclear, although a central role for mitochondria is proposed. We investigated the effects of TKIs on cellular metabolism in muscle biopsies of CML patients (n = 20), compared with healthy controls (n = 10) and whether these changes may be linked to muscle complaints. C2C12 myotubes were used to further explore the effects of TKIs on muscle metabolism in vitro. We found that TKI muscle concentrations in CML patients aligned with the concentrations at which cytotoxicity could be observed in C2C12 myotubes, and that muscle to plasma ratios tended to correlate with the degree of MC in CML patients. In C2C12 myotubes, acute TKI incubation of C2C12 myotubes resulted in alterations in energy metabolism, showing a shift from glycolysis to oxidative phosphorylation. CML patients without MC showed higher oxidative capacity, characterized by higher mitochondrial complex activities in skeletal muscle and occurrence of the first ventilatory threshold at a higher percentage of peak oxygen uptake during maximal exercise compared to patients with MC. Taken together, these observations raise the possibility that TKIs may affect cellular energy metabolism and may contribute to muscle complaints.Trial registration The Netherlands Trial Registry identifier NTR6373.

Keywords:  Chronic myeloid leukemia; Energy metabolism; Mitochondrial function; Muscle complaints; Tyrosine kinase inhibitors

DOI:  https://doi.org/10.1007/s00421-026-06287-6
J Neuromuscul Dis. 2026 Jun 03. 22143602261458436

MDBiomarkers: A queryable biomarkers database integrating multiple serum and tissue datasets for Duchenne muscular dystrophy.

Wangshu Tu, Rebecca A Tobin, Leenah Abdelrazeq, Kaitey Guite, Cristina Al-Khalili Szigyarto, Roula Tsonaka, Chiara Degan, Yuri E M van der Burgt, Jordi Díaz-Manera, Michela Guglieri, Pietro Spitali, Yetrib Hathout, Utkarsh J Dang.

  BackgroundFit-for-purpose biomarkers are urgently needed in Duchenne muscular dystrophy (DMD). However, biomarker efforts in DMD have traditionally been hampered by a lack of reproducibility due to small sample sizes, confounders such as treatment and age, and discordant findings from different technologies. Moreover, there is no central resource to get an overview of cumulative published evidence. Hence, many researchers often start with new discovery studies, which are time-consuming and costly.ObjectiveBuild a dynamic, searchable, and easy-to-use biomarker platform for DMD.MethodsThousands of molecular (serum proteins and muscle mRNA) markers from multiple studies (28 analyses) were compiled. Findings were obtained from supplemental material of published manuscripts or by following standardized pipelines on available raw data. These findings were annotated with important attributes (e.g., age range, treatment, etc.). Evidence was aggregated around each biomarker's association with DMD, treatment, age, clinical outcomes, as well as other markers.ResultsThe interactive Shiny application on https://www.mdbiomarkers.com provides exportable summaries of serum protein and muscle tissue mRNA findings. This also permits new knowledge to be generated for nuanced meta-analyses, rather than being restricted by a single study's finding and p-value. A tutorial is provided on the website. This resource is planned to be continually updated with new/additional findings to fulfill the aim of a living biomarker resource.ConclusionsThe resource developed will reduce preparatory time to distill evidence around important biomarker candidates providing summary estimates around individual studies' effect sizes, help assess cumulative evidence, and help with experimental design of future experiments.

Keywords:  DMD biomarker database; Duchenne muscular dystrophy; Shiny application; biomarker associations; biomarker website; mRNA; proteomics; reproducibility; serum; tissue

DOI:  https://doi.org/10.1177/22143602261458436