bims-moremu 2025-07-06 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–07–06
38 papers selected by
Anna Vainshtein, Craft Science Inc.

Skeletal muscle proteomics: considerations and opportunities.
Are Masters athletes the gold standard of ageing?
Aerobic and resistance exercise-regulated phosphoproteome and acetylproteome modifications in human skeletal muscle.
RCOR1 promotes myoblast differentiation and muscle regeneration.
Muscle-specific AXIN1 and AXIN2 double knockout does not alter AMPK/mTORC1 signalling or glucose metabolism.
Brief ambulatory reloading elevates muscle protein synthesis but does not prevent disuse atrophy in hindlimb-unloaded rats.
Inactivity-induced NR4A3 downregulation in human skeletal muscle affects glucose metabolism and translation: insights from in vitro analysis.
Modulation of Wnt/β-Catenin Signaling by STAT3 Inhibition Restores Myogenic Capacity in Sarcopenia.
Altered Relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)Adaptations in Aging Skeletal Muscle and Are Prevented by Exercise.
The TWEAK/Fn14 signaling mediates skeletal muscle wasting during cancer cachexia.
Unraveling Skeletal Muscle Insulin Resistance: Molecular Mechanisms and the Restorative Role of Exercise.
Systematic identification of exercise-induced anti-aging processes involving intron retention.
Long non-coding RNAs Kcnq1ot1 and Lncpint are involved in skeletal muscle atrophy induced by the space exposome.
Interplay between microtubule interactome, myonuclei mechanotransduction, and positioning in myopathies.
Bioactive lipid mediator class switching regulates myogenic cell progression and muscle regeneration.
Time-of-day effect of high-intensity muscle contraction on mTOR signaling and protein synthesis in mice.
Abnormalities in the genioglossus muscle and its neuromuscular synapse in leptin-deficient male mice.
Muscle Rev-erb controls time-dependent adaptations to chronic exercise in mice.
Fibro-adipogenic progenitors prevent skeletal muscle degeneration at acute phase upon tendon rupture in a murine tibialis anterior tenotomy model.
L-NAME improves the morphology and necrosis of skeletal muscle by activating PINK1-PARKIN mediated mitophagy in mdx mice.
Grb2/Sos1 signaling regulates the number of reserve cells in C2C12 cell culture.
Evaluating skeletal muscle wasting and weakness in models of critical illness.
PGC-1 alpha overexpression in the skeletal muscle results in a metabolically active microbiome which is independent of redox signaling.
Advancements in skeletal muscle tissue engineering: strategies for repair and regeneration of skeletal muscle beyond self-repair.
Injectable borax-loaded alginate hydrogels reduce muscle atrophy, modulate inflammation, and promote neuroprotection in the SOD1G93A mouse model of ALS through mechanisms involving IGF-Akt-mTOR signaling.
Striatal Dopamine and Skeletal Muscle Energy Metabolism in Older Adults.
Pancreatic Cancer-Derived Extracellular Vesicles Enriched with miR-223-5p Promote Skeletal Muscle Wasting Associated with Cachexia.
Dorothy Hodgkin lecture 2024: Insulin regulation of mitochondrial biogenesis and function-Impact of dysregulation of mitochondrial function in diabetes and its complications.
Decoding Cellular Communication Networks and Signaling Pathways in Bone, Skeletal Muscle, and Bone-Muscle Crosstalk Through Spatial Transcriptomics.
Muscle spindle afferent neurons preferentially degenerate with aging.
Iron supplementation alleviates pathologies in a mouse model of facioscapulohumeral muscular dystrophy.
Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis.
Effect of transforming growth factor beta receptor I inhibitors on myotube formation in vitro.
Muscle needs NAD, but how much?
WNT5B regulates myogenesis and fiber type conversion by affecting mRNA stability.
The impact of mitokine MOTS-c administration on the soleus muscle of rats subjected to a 7-day hindlimb suspension.
Molecular mechanism of Activin receptor inhibition by DLK1.
A review: oxidative stress in skeletal muscle and the non-coding RNAs behind it.

npj metabolic health and disease... 2025 Jul 02. 3(1): 30

Skeletal muscle proteomics: considerations and opportunities.

Julian P H Wong, Yaan-Kit Ng, Jeppe Kjærgaard, Ronnie Blazev, Atul S Deshmukh, Benjamin L Parker.

Skeletal muscle accounts for 30-40% of body weight and plays an indispensable role in maintaining movement and is also a central regulator of whole-body metabolism. As such, understanding the molecular mechanisms of skeletal muscle health and disease is vital. Proteomics has been revolutionized in recent years and provided new insights into skeletal muscle. In this review, we first highlight important considerations unique to the field which make skeletal muscle one of the most challenging tissues to analyse by mass spectrometry. We then highlight recent advances using the latest case studies and how this has allowed coverage of the skeletal muscle temporal, fibre type and stem cells proteome. We also discuss how exercise and metabolic dysfunction can remodel the muscle proteome. Finally, we discuss the future directions of the field and how they can be best leveraged to increase understanding of human biology.

DOI: https://doi.org/10.1038/s44324-025-00073-2
J Physiol. 2025 Jun 30.

Are Masters athletes the gold standard of ageing?

Dominique Greyvenstein, James P Newbold, Brandan K Wilson.



Keywords:  Masters athletes; ageing; exercise; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1113/JP289005
Nat Commun. 2025 Jul 01. 16(1): 5700

Aerobic and resistance exercise-regulated phosphoproteome and acetylproteome modifications in human skeletal muscle.

Mark W Pataky, Carrie J Heppelmann, Kyle J Sevits, Aneesh K Asokan, Arathi Prabha Kumar, Katherine A Klaus, Surendra Dasari, Hawley E Kunz, Matthew D Strub, Matthew M Robinson, Joshua J Coon, Ian R Lanza, Christopher M Adams, K Sreekumaran Nair.

Despite indisputable benefits of different exercise modes, the molecular underpinnings of their divergent responses remain unclear. We investigate post-translational modifications in human skeletal muscle following 12 weeks of high-intensity aerobic interval or resistance exercise training. High-intensity aerobic training induces acetylproteome modifications including several mitochondrial proteins, indicating post-translational regulation of energetics machinery, whereas resistance exercise training regulates phosphoproteomic modifications of contractile/cytoskeletal machinery, consistent with greater strength. Furthermore, despite similar transcriptional responses to a single acute bout of aerobic and resistance exercise, more robust phosphoproteomic and metabolomic responses occur with acute aerobic exercise, including phosphorylation of structural/contractile and membrane transport machinery, and the nascent polypeptide-associated complex-α, a regulator of protein translation. Together, our findings provide new insight on the intricate phosphoproteomic and acetylproteomic modifications in muscle that potentially explain physiological responses to different modes of chronic and acute exercise. This study is registered with ClinicalTrials.gov, numbers NCT01477164 and NCT04158375.

DOI: https://doi.org/10.1038/s41467-025-60049-0
Cell Death Discov. 2025 Jul 01. 11(1): 298

RCOR1 promotes myoblast differentiation and muscle regeneration.

Martina Pauk, Fan Wang, Petri Rummukainen, H G Mauricio Ramm, Hanna Taipaleenmäki, Riku Kiviranta.

RCOR proteins belong to a family of highly conserved transcription corepressors (RCOR1, RCOR2 and RCOR3) that regulate the activity of associated histone demethylase 1 (LSD1) and histone deacetylase 1/2 (HDAC 1/2) in chromatin-modifying complexes. Despite the described function of LSD1 in skeletal muscle differentiation and regeneration, the role of RCOR family in myogenesis remains unknown. We found that RCOR1 is highly expressed in proliferating myoblasts and activated satellite cells, but not in mature myofibers during postnatal skeletal muscle growth and regeneration. Silencing of RCOR1 impaired myoblast differentiation and fusion, as evidenced by reduced levels of myogenin and MyHC, key markers of myogenic commitment. Moreover, RCOR1 depletion impaired myoblast proliferation through upregulation of the cell cycle inhibitor P21. Although combined silencing of P21 and RCOR1 rescued the proliferation defect of RCOR1 deficiency alone, it failed to restore differentiation, suggesting that RCOR1 action on myoblast proliferation and differentiation is mediated via independent mechanisms. RCOR1 was found physically associated with LSD1 and myogenic regulatory factor MyoD and contributed to LSD1 stability in myoblasts via ubiquitination. Accordingly, the repressive effect of RCOR1 depletion on myogenic differentiation was rescued by LSD1 overexpression, indicating that RCOR1 exerts its function on myoblast differentiation primarily through LSD1. Consistently, in a mouse model of skeletal muscle injury, depletion of RCOR1, accompanied with reduction of LSD1, supressed satellite cell activation and differentiation which resulted in impaired muscle regeneration. Together, our findings indicate that RCOR1 acts in concert with LSD1 as a novel positive regulator of myogenesis and skeletal muscle regeneration.

DOI: https://doi.org/10.1038/s41420-025-02568-9
J Physiol. 2025 Jun 30.

Muscle-specific AXIN1 and AXIN2 double knockout does not alter AMPK/mTORC1 signalling or glucose metabolism.

Kaspar W Persson, Roberto Meneses-Valdés, Nicoline R Andersen, Frederik S Pedersen, Samantha Gallero, Sofie A Hesselager, Carlos Henriquez-Olguin, Thomas E Jensen.

  AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) are crucial kinase signalling hubs that regulate the balance between catabolism and anabolism in skeletal muscle. The scaffold protein AXIN1 has been proposed to regulate the switch between these pathways and be required for GLUT4 translocation in skeletal muscle and adipocyte cell lines. Muscle-specific AXIN1 knockout (KO) mice exhibit no discernable phenotype, possibly due to compensation by AXIN2 upon AXIN1 loss. Thus we generated and characterized muscle-specific inducible AXIN1 and AXIN2 double knockout (dKO) mice. Surprisingly AXIN1/2 dKO mice displayed normal AMPK and mTORC1 signalling and glucose uptake in response to 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), insulin and in situ muscle contraction. These findings suggest that AXIN proteins are not essential for the regulation of AMPK and mTORC1 signalling or glucose uptake in skeletal muscle. This study challenges the previously indicated critical roles of AXIN1 in exercise-stimulated AMPK activation and GLUT4-mediated glucose uptake in skeletal muscle. KEY POINTS: Phenotyping of tamoxifen-inducible muscle-specific AXIN1/2 double knockout (dKO) mice. We find no evidence for AXIN-dependent AMPK or mTORC1 regulation in skeletal muscle by insulin, AMPK activation or contraction. Glucose uptake regulation by insulin and AMPK activation is normal in AXIN1/2 dKO mice.

Keywords:  AMPK; exercise; glucose transport; mTOR; skeletal muscle

DOI:  https://doi.org/10.1113/JP288854
Biochem Biophys Rep. 2025 Sep;43 102100

Brief ambulatory reloading elevates muscle protein synthesis but does not prevent disuse atrophy in hindlimb-unloaded rats.

Michael P Wiggs, Carla Mc Nascimento, Kevin L Shimkus, James D Fluckey.

  Disuse muscle atrophy remains a major challenge in contexts such as prolonged bed rest or microgravity. Here, we investigated whether brief bouts of ambulatory reloading could attenuate skeletal muscle atrophy caused by five days of hindlimb unloading (HU) in rats. Using a deuterium oxide tracer, we measured integrative protein synthesis (fractional synthesis rate, FSR) in the soleus, plantaris, and gastrocnemius muscles, including distinct portions of the muscle that are composed mostly of red, white, and mixed fibers. HU significantly reduced both muscle mass and FSR in the predominantly slow-twitch soleus and in the predominantly fast gastrocnemius. Intermittent ambulatory reloading (HU + AR) partially restored FSR in the soleus and gastrocnemius but did not recover soleus or gastrocnemius mass to control levels. The plantaris muscle showed no differences in mass or FSR among groups, suggesting muscle-specific responses to unloading and reloading. Fiber-type analyses revealed that portions of the gastrocnemius that are mostly red fibers had higher baseline FSR than mixed or white portions, while HU consistently depressed protein synthesis across all fiber types. In conclusion, although intermittent ambulation increased protein synthesis during HU, it was not sufficient to prevent overall muscle mass loss. These findings emphasize the importance of both the duration and intensity of loading in preserving skeletal muscle during periods of disuse.

Keywords:  Anabolic signaling; Countermeasures; Microgravity; Spaceflight

DOI:  https://doi.org/10.1016/j.bbrep.2025.102100
Mol Metab. 2025 Jul 01. pii: S2212-8778(25)00107-3. [Epub ahead of print] 102200

Inactivity-induced NR4A3 downregulation in human skeletal muscle affects glucose metabolism and translation: insights from in vitro analysis.

Jonathon A B Smith, Brendan M Gabriel, Aidan J Brady, Ahmed M Abdelmoez, Mladen Savikj, Shane C Wright, Stefania Koutsilieri, Romain Barrès, Volker M Lauschke, Anna Krook, Juleen R Zierath, Nicolas J Pillon.

   BACKGROUND: Physical activity promotes health, whereas inactivity is associated with metabolic impairment. The transcription factor nuclear receptor subfamily 4 group A member 3 (NR4A3) is a pleiotropic regulator of skeletal muscle exercise adaptation and metabolism. However, the consequence of lower NR4A3 expression remains largely unexplored. We investigated the impact of NR4A3 downregulation on human skeletal muscle metabolism.
METHODS: Published transcriptomic datasets from human bed rest and limb immobilisation studies were curated to meta-analyse the effect of physical inactivity on skeletal muscle NR4A3 levels. In primary human skeletal myotubes, siRNA and lentivirus were used to silence and overexpress NR4A3, respectively. Basal and stimulated (insulin ± leucine) signal transduction was determined by immunoblot analysis. Effects on glucose, fatty acid, and protein metabolism were measured using radiolabelled substrate assays. Lactate production was assessed in culture supernatant by colourimetry. Cell morphology was analysed by immunocytochemistry and gene expression was quantified by RT-qPCR.
RESULTS: Physical inactivity decreased skeletal muscle NR4A3 (-27%), concomitant with pathways related to mitochondrial function, cytoskeleton organization, chromatin regulation, protein synthesis and degradation. Silencing of nuclear-localised NR4A3 protein (-30%) reduced glucose oxidation (-18%) and increased lactate production (+23%) in vitro. This coincided with greater signalling downstream of AMPK and elevated rates of basal (+26%) and FCCP-stimulated (+55%) fatty acid oxidation. NR4A3 downregulation lowered protein synthesis (-25%), and impaired mTORC1 signalling and ribosomal transcription. Alternatively, overexpression of the canonical NR4A3 protein isoform (+290%) augmented translation and total cellular protein content, which protected myotubes against dexamethasone-induced atrophy. Moreover, partial restoration of NR4A3 levels rescued glucose oxidation in NR4A3-silenced muscle cells and restored phosphorylation of mTORC1 substrates. NR4A3 depletion reduced myotube area (-48%) and further altered protein and gene expression of key contractile elements in skeletal muscle.
CONCLUSIONS: Our study connects reduced NR4A3 expression with physical inactivity and indicates that NR4A3 downregulation in human skeletal muscle has adverse effects on glucose metabolism and protein synthesis. Thus, decrements in NR4A3 abundance could be causal in the deleterious health consequences resulting from sedentary lifestyles and targeting NR4A3 may offer new avenues for combating conditions such as disuse muscle atrophy.

Keywords:  Skeletal muscle; inactivity; metabolism; mitochondria; protein synthesis

DOI:  https://doi.org/10.1016/j.molmet.2025.102200
Int J Rheum Dis. 2025 Jul;28(7): e70340

Modulation of Wnt/β-Catenin Signaling by STAT3 Inhibition Restores Myogenic Capacity in Sarcopenia.

Suhong Zhang, Xin Tao, Minghui Fu, Yue Li, Gongbing Tu, Dianfu Zhang, Liping Yin.

   BACKGROUND: Sarcopenia is a progressive disorder characterized by loss of skeletal muscle mass, strength, and function. Although STAT3 is known to regulate myogenic differentiation, its role in sarcopenia remains unclear.
METHODS: STAT3 expression was assessed in skeletal muscle samples from sarcopenia patients and nonsarcopenic controls, as well as aged SAMP8 mice. C2C12 myoblasts were used to investigate the effects of STAT3 on proliferation and myogenic differentiation using gain- and loss-of-function approaches. The role of the Wnt/β-catenin pathway was examined using pathway-specific assays. In vivo, siRNA-mediated STAT3 knockdown was performed in aged SAMP8 mice to evaluate effects on muscle phenotype and endurance.
RESULTS: STAT3 expression was significantly upregulated in muscle tissues from sarcopenia patients and aged mice, correlating with increased expression of the atrophy marker MuRF-1. STAT3 levels also rose during C2C12 cell differentiation. STAT3 overexpression suppressed C2C12 proliferation and myogenic differentiation, whereas knockdown enhanced both processes. Mechanistically, STAT3 inhibited Wnt/β-catenin signaling, reducing the expression of myogenic markers. In vivo, STAT3 silencing in aged mice increased muscle mass, improved treadmill performance, and decreased muscle atrophy markers.
CONCLUSION: STAT3 impairs myogenic proliferation and differentiation by negatively regulating the Wnt/β-catenin pathway, contributing to sarcopenia progression. Targeting STAT3 may serve as a promising therapeutic strategy for restoring muscle regeneration and function in sarcopenia.

Keywords:  C2C12; STAT3; Wnt/β‐catenin; muscle mass; myogenic differentiation; sarcopenia

DOI:  https://doi.org/10.1111/1756-185X.70340
Aging Cell. 2025 Jun 30. e70137

Altered Relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)Adaptations in Aging Skeletal Muscle and Are Prevented by Exercise.

Ryan J Allen, Ana Kronemberger, Qian Shi, R Marshall Pope, Elizabeth Cuadra-Muñoz, Wangkuk Son, Long-Sheng Song, Ethan J Anderson, Renata O Pereira, Vitor A Lira.

  Sarcopenia, or age-related muscle dysfunction, contributes to morbidity and mortality. Besides decreases in muscle force, sarcopenia is associated with atrophy and fast-to-slow fiber type switching, which is typically secondary to denervation in humans and rodents. However, very little is known about cellular changes preceding these important (mal)adaptations. To this matter, mitochondria and the sarcoplasmic reticulum are critical for tension generation in myofibers. They physically interact at the boundaries of sarcomeres, forming subcellular hubs called mitochondria-endo/sarcoplasmic reticulum contacts (MERCs). Yet, whether changes at MERCs ultrastructure and proteome occur early in aging is unknown. Here, studying young adult and older mice, we reveal that aging slows muscle relaxation, leading to longer excitation-contraction-relaxation (ECR) cycles before maximal force decreases and fast-to-slow fiber switching takes place. We also demonstrate that muscle MERC ultrastructure and mitochondria-associated ER membrane (MAM) protein composition are affected early in aging and are closely associated with the rate of muscle relaxation. Additionally, we demonstrate that regular exercise preserves muscle relaxation rate and MERC ultrastructure in early aging. Finally, we profile a set of muscle MAM proteins involved in energy metabolism, protein quality control, Ca2+ homeostasis, cytoskeleton integrity, and redox balance that are inversely regulated early in aging and by exercise. These may represent new targets to preserve muscle function in aging individuals.

Keywords:  aging; endoplasmic reticulum; exercise; mitochondria; mitochondrial‐associated ER membranes; sarcopenia; sarcoplasmic reticulum; skeletal muscle

DOI:  https://doi.org/10.1111/acel.70137
iScience. 2025 Jul 18. 28(7): 112714

The TWEAK/Fn14 signaling mediates skeletal muscle wasting during cancer cachexia.

Meiricris Tomaz da Silva, Anirban Roy, Anh Tuan Vuong, Aniket S Joshi, Cristeena Josphien, Meghana V Trivedi, Sajedah M Hindi, Vihang A Narkar, Ashok Kumar.

  Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting. The TWEAK-Fn14 system regulates muscle mass in diverse conditions. However, its role in the regulation of muscle mass during cancer cachexia remains less understood. Here, we demonstrate that the levels of Fn14 are induced in skeletal muscle of multiple mouse models of cancer cachexia. Muscle-specific deletion of Fn14 reduces myofiber atrophy in mouse models of pancreatic and lung cancer cachexia. Silencing of Fn14 in KPC pancreatic cancer cells prior to their implantation in mice attenuates tumor growth without affecting myofiber size. Muscle-specific deletion of Fn14 reduces the gene expression of various components of the PERK and IRE1α arms of the unfolded protein response during KPC tumor growth. The inhibition of PERK improves protein synthesis and average myotube diameter in TWEAK-treated cultures. Altogether, our study suggests that the inhibition of TWEAK/Fn14 signaling can attenuate tumor growth and muscle wasting during cancer cachexia.

Keywords:  Cancer; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.112714
Circ Res. 2025 Jul 07. 137(2): 184-204

Unraveling Skeletal Muscle Insulin Resistance: Molecular Mechanisms and the Restorative Role of Exercise.

Katie L Whytock, Bret H Goodpaster.

  Skeletal muscle is essential for movement and maintaining energy homeostasis and is the primary tissue for insulin-stimulated glucose uptake. Skeletal muscle is composed of various cell types that help to govern the delivery, transport, and metabolism of nutrients to and within the tissue. Dysregulation of these processes can result in impaired insulin-stimulated glucose uptake and dysglycemia-insulin resistance and type 2 diabetes. Acute exercise and chronic exercise training provide a robust stimulus to improve nutrient delivery, nutrient transport into a cell, and subsequent storage and oxidation to help improve insulin sensitivity. This review details the molecular mechanisms of skeletal muscle insulin resistance and how exercise counteracts these defects, highlighting the key role of exercise in muscle health and disease.

Keywords:  exercise; glucose; homeostasis; insulin resistance; muscle, skeletal

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.325532
J Gerontol A Biol Sci Med Sci. 2025 Jul 04. pii: glaf146. [Epub ahead of print]

Systematic identification of exercise-induced anti-aging processes involving intron retention.

Hayata Kodama, Hirotaka Ijima, Yusuke Matsui.

  Exercise is one of the most promising anti-aging interventions for maintaining skeletal muscle health in older adults. Nine "Aging Hallmarks", proposed by López-Otín, offer insights into the aging process; however, the link between these hallmarks and exercise is not fully elucidated. In this study, we conducted a systematic multi-omics analysis of skeletal muscles, focusing on aging and exercise, based on gene signatures for aging hallmarks. It is posited that mRNA splicing activity, linked to genomic instability, constitutes a fundamental hallmark of aging, and exhibits divergent expression patterns in response to aging and exercise. Additionally, we analyzed splicing events and discovered that intron retention (IR) is significantly impacted by aging, exhibiting contrasting changes to those induced by resistance training in the older cohort. The isoforms characterized by IR are notably enriched in mitochondrial functions. Conclusively, our results underscore the significance of splicing mechanisms as a novel aspect of aging hallmarks in skeletal muscles and propose a new mechanism by which exercise exerts its anti-aging effects on skeletal muscles through IR.

Keywords:  Aging Hallmarks; exercise; genomic instability; intron retention; mRNA splicing; skeletal muscle aging

DOI:  https://doi.org/10.1093/gerona/glaf146
J Physiol. 2025 Jun 29.

Long non-coding RNAs Kcnq1ot1 and Lncpint are involved in skeletal muscle atrophy induced by the space exposome.

Sergio Pérez-Díaz, Bjorn Baselet, Alen Lovric, Tommy R Lundberg, Mieke Neefs, Lisa Daenen, Eric Rullman, Rodrigo Fernandez-Gonzalo.

  Long non-coding RNAs (lncRNAs) play an important role in the regulation of skeletal muscle transcriptional processes, but their involvement in spaceflight- or inactivity-induced muscle atrophy remains poorly understood. To address this gap we simulated the space environment by combining microgravity, irradiation and stress in a mouse model. This simulation resulted in the differential expression (threshold set at P < 0.01) of 6191 protein-coding genes (3525 downregulated and 2666 upregulated compared to controls) and 465 lncRNAs, of which 27% were downregulated and 73% upregulated compared to controls. Particularly several previously identified lncRNAs involved in muscle regulation were affected, including H19 (log fold change, logFC: -2.0), Gm29773 (logFC: -1.4), Pvt1 (logFC: 0.63), Kcnq1ot1 (logFC: 0.31) and Lncpint (logFC: 0.86). To determine whether similar changes occurred in humans, we examined the expression of lncRNAs during long-term (3 months) head-down tilt bed rest, a model for microgravity-induced muscle atrophy. We found that Kcnq1ot1 and Lncpint (human homologues KCNQ1OT1 and LINC-PINT) were upregulated in response to simulated microgravity. In addition KCNQ1OT1 was increased in a human 3-D in vitro model of muscle atrophy. These results are the first to demonstrate the involvement of lncRNAs in spaceflight- and severe inactivity-induced muscle atrophy, in particular KCNQ1OT1 and LINC-PINT. Our study provides novel insights into the contribution of lncRNAs to muscle atrophy caused by the space exposome and has broader implications for understanding and combating muscle atrophy in clinical scenarios of prolonged inactivity. Future research can build on these findings to investigate the therapeutic potential of lncRNAs in muscle atrophy. KEY POINTS: The combination of unloading, irradiation and stress led to a significant reduction in skeletal muscle mass and marked transcriptional responses (6191 differentially expressed genes) in the skeletal muscle of mice. The simulated space exposome led to the differential expression of 465 long non-coding RNAs (lncRNAs) in mouse skeletal muscle. Two lncRNAs upregulated in mice - Kcnq1ot1 and Lncpint - were also upregulated in human muscle after 3 months of bed rest (human homologues KCNQ1OT1 and LINC-PINT). KCNQ1OT1, but not LINC-PINT, was upregulated in a human 3-D in vitro model of muscle atrophy. This study offers fundamental insights into the role of lncRNAs in muscle atrophy induced by the space exposome. These findings have broader implications for understanding and mitigating muscle atrophy in clinical settings, such as prolonged inactivity.

Keywords:  RNA sequencing; bed rest; lncRNA; skeletal muscle; spaceflight analogues; transcriptional regulation

DOI:  https://doi.org/10.1113/JP288987
Nucleus. 2025 Dec;16(1): 2524909

Interplay between microtubule interactome, myonuclei mechanotransduction, and positioning in myopathies.

Léa Castellano, Damien Caillol, Nathalie Streichenberger, Vincent Gache.

  Myofibers are the building block of skeletal muscle cells providing its capacity to contract and produce movement. The microtubule (MT) network sustains myofiber formation and its spatial organization is remodel during myofiber formation. This muscle-related MT network with specific partners, actively drive myonuclei localization in myofiber. In pathological conditions, myonuclei and MT patterning are affected and contribute to skeletal muscle mis-functionality. In this review, we classified myopathies depending on myonuclei positioning within myofibers and reported that 72% of myopathies exhibit myonuclei positioning alterations. We explored how this impairment can be analyzed according to muscle disease development, MT alterations and association with various partners. We highlighted how MT modifications impact muscle-specific mechanotransduction status and myofiber functional integrity. We then reported genes involved in myonuclei shape and positioning maintenance. Finally, we discussed technical contribution advances in the field to improve knowledge on muscle physiology and its challenges in disease context.

Keywords:  Cytoskeleton; maps; mechanotransduction; microtubule network; myofiber; myonuclear domain; myonuclei; myopathies; skeletal muscle; transcriptomics

DOI:  https://doi.org/10.1080/19491034.2025.2524909
Nat Commun. 2025 Jul 01. 16(1): 5578

Bioactive lipid mediator class switching regulates myogenic cell progression and muscle regeneration.

Paul Fabre, Thomas Molina, Jessica Larose, Karine Greffard, Gregory Généreux-Gamache, Alyson Deprez, Inès Mokhtari, Ornella Pellerito, Elise Duchesne, Junio Dort, Jean-François Bilodeau, Nicolas A Dumont.

The muscle stem cell niche is well-described as influencing myogenic cell fate decision; however, the intrinsic mechanisms driving muscle stem cell progression during myogenesis are not yet fully elucidated. Here, we demonstrate that bioactive lipid class switching, an auto-regulatory mechanism originally described during the inflammatory process, is conserved during myogenesis. During the transition from proliferation to differentiation, myogenic cells shift from pro-inflammatory to pro-resolution pathways, a process partially mediated by 15Δ-PGJ2 that promotes the expression of the prostaglandin inactivation enzyme 15-hydroxyprostaglandin dehydrogenase. Using pharmacological inhibitors and knockout models of the pro-resolution enzyme 15-lipoxygenase, we show that blocking the bioactive lipid class switching impairs myoblast differentiation in vitro and muscle regeneration in vivo. Administration of the pro-resolving mediator Protectin-D1 restores myogenesis, enhances muscle regeneration post-injury and improves muscle phenotype in a dystrophic mouse model. Overall, these findings provide a better comprehension of the mechanisms regulating myogenic progression, which opens new therapeutic avenues for muscle regeneration and dystrophies.

DOI: https://doi.org/10.1038/s41467-025-60586-8
Sci Rep. 2025 Jul 03. 15(1): 23702

Time-of-day effect of high-intensity muscle contraction on mTOR signaling and protein synthesis in mice.

Taiga Mishima, Yosuke Takenaka, Akiko Hashimoto-Hachiya, Yukiko Tanigawa, Natsumi Suzuki, Katsutaka Oishi, Riki Ogasawara.

  Resistance exercise promotes muscle protein synthesis by activating mechanistic target of rapamycin (mTOR). The magnitude of muscle hypertrophy might differ depending on the timing of resistance exercise, but the molecular mechanism remains unclear. We aimed to define whether the time of day when muscles are contracted affects mTOR signaling and muscle protein synthesis. Adult male C57BL/6 J mice were housed under a 12 h/12 h light/dark cycle, and right gastrocnemius muscles were contracted using percutaneous electrical stimulation at 1, 7, 13, or 19 h after lights on. Contractions induced more phosphorylation of downstream targets of mTOR complex 1 (mTORC1) signaling such as S6K1 and rpS6 during the light (sleep), than the dark (active) phase, while expression of the negative regulator of mTORC1 that regulates development and DNA damage responses 1 (REDD1) was anti-phasic. Basal muscle protein synthesis in the sedentary leg was higher during the light, compared to the dark phase, while contraction-induced synthesis did not significantly vary throughout the day. Muscle hypertrophy is controlled by the balance between protein synthesis and degradation. Therefore, further studies are needed to elucidate the time-of-day effects of resistance exercise on muscle hypertrophy.

Keywords:  Circadian rhythm; Muscle contraction; Protein synthesis; mTOR

DOI:  https://doi.org/10.1038/s41598-025-06709-z
Skelet Muscle. 2025 Jul 05. 15(1): 18

Abnormalities in the genioglossus muscle and its neuromuscular synapse in leptin-deficient male mice.

Srujith Medharametla, Garrett Borger, Shashir Gaonkar, Isabel Martinez-Pena Y Valenzuela.

BACKGROUND: The genioglossus (GG) muscle, the largest upper airway dilator muscle, plays a crucial role in maintaining pharyngeal airway patency. It is innervated by hypoglossal motoneurons, and its tone is often reduced in patients with obstructive sleep apnea (OSA), leading to tongue collapse and airway obstruction during sleep. Although the mechanisms underlying this disorder are not fully understood, the neuromuscular junction (NMJ) of the GG muscle, essential for communication between motor neurons and skeletal muscle, has largely been overlooked.
METHODS: In this study, we explored whether obesity impacts the NMJ of the GG muscle. Using the leptin-deficient obese mouse model, Lepob/ob, which exhibits pharyngeal collapsibility and hypoventilation, we analyzed the GG muscle and its NMJ in both male and female mice. We conducted morphological and histochemical studies of the GG muscle; quantitative fluorescence imaging to assess the density and dynamics of nicotinic acetylcholine receptors (nAChRs) at the NMJ; high-resolution confocal microscopy to evaluate structural changes in the pre- and postsynaptic apparatus; and transmission electron microscopy for ultrastructural analysis. Additionally, we examined the diaphragm (DIA) and sternomastoid (ST) muscles for comparative analysis.
RESULTS: Our results show that the GG muscle and its NMJs exhibit significant alterations in Lepob/ob male mice, while the ST and DIA muscles remain unaffected. Lepob/ob males displayed altered GG muscle morphology, changes in synapse structure, and reduced postsynaptic AChR density compared to both controls and Lepob/ob females. Additionally, AChR turnover and the morphology of the presynaptic apparatus were impaired in Lepob/ob male mice. In contrast, Lepob/ob females exhibited NMJs similar to those of wild-type mice.
CONCLUSIONS: These findings suggest that the GG muscle is particularly susceptible to degeneration in obesity induced by leptin deficiency, with distinct alterations observed in both the muscle and the NMJ. This specificity underscores the complex impact of obesity on NMJ health and highlights the need for further investigation into muscle-specific responses to obesity-related stress. Additionally, the degeneration of the GG muscle appears to reflect a sex-specific impact of obesity on neuromuscular integrity and may contribute to the pathogenesis of OSA.

DOI: https://doi.org/10.1186/s13395-025-00387-1
Nat Commun. 2025 Jul 01. 16(1): 5708

Muscle Rev-erb controls time-dependent adaptations to chronic exercise in mice.

Jidong Liu, Fang Xiao, Abhinav Choubey, Udhaya Kumar S, Yanxiang Wang, Sungguan Hong, Tingting Yang, Husniye Gul Otlu, Ege Sanem Oturmaz, Emanuele Loro, Yuxiang Sun, Pradip Saha, Tejvir S Khurana, Li Chen, Xinguo Hou, Zheng Sun.

The best time of the day for chronic exercise training and the mechanism underlying the timing effects is unclear. Here, we show that low-intensity, low-volume treadmill training in mice before sleep yields greater benefits than after waking for muscle contractile performance and systemic glucose tolerance. Baseline muscle performance also exhibits diurnal variations, with higher strength but lower endurance before sleep than after waking. Muscle-specific knockout of circadian clock genes Rev-erbα/β (Rev-MKO) in male mice eradicates the diurnal variations in both training and baseline conditions without affecting muscle mass, mitochondrial content, food intake, or spontaneous activities. Multi-omics and metabolic measurements reveal that Rev-erb suppresses fatty acid oxidation and promotes carbohydrate metabolism before sleep. Thus, the muscle-autonomous clock, not feeding or locomotor behaviors, dictates diurnal variations of muscle functions and time-dependent adaptations to training, which has broad implications in metabolic disorders and sports medicine as Rev-erb agonists are exercise mimetics or enhancers.

DOI: https://doi.org/10.1038/s41467-025-60520-y
World J Stem Cells. 2025 Jun 26. 17(6): 105491

Fibro-adipogenic progenitors prevent skeletal muscle degeneration at acute phase upon tendon rupture in a murine tibialis anterior tenotomy model.

Zhe-Ci Ding, Juan-Juan He, Lu-Ze Shi, Jin Qian, Shu-Hao Mei, Xia Kang, Ji-Wu Chen.

   BACKGROUND: Fibro-adipogenic progenitors (FAPs) are a group of mesenchymal stem cells that cause fibro-fatty degeneration in skeletal muscle in various chronic disease models. FAPs also play a role in preventing muscle degeneration at acute stages during disease progression. However, few studies have reported the changes in and function of FAPs in the acute phase after tendon rupture.
AIM: To clarify the changes in the number of FAPs and their impact on skeletal muscle soon after tendon rupture to facilitate future studies targeting FAPs to treat muscle degeneration.
METHODS: We utilized Pdgfra-H2B::eGFP mice to trace and quantify FAPs in a tibialis anterior tenotomy (TAT) model at 0 and 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, and 6 weeks post-injury, and the results were further validated using fluorescence-activated cell sorting analysis with C57BL/6 mice at the same post-injury timepoints. We subsequently used PdgfraCreERT::RosaDTA mice, and evaluated the severity of post-TAT skeletal muscle degeneration with or without FAP-depletion.
RESULTS: The number of FAPs peaked at 1 week post-TAT before gradually declining to a level comparable to that pre-TAT. The change in the number of FAPs was potentially temporally correlated with the progression of skeletal muscle degeneration after TAT. FAP-depletion led to more severe degeneration early after TAT, indicating that FAPs potentially alleviate muscle degeneration after tendon rupture in the early post-injury phase.
CONCLUSION: FAPs potentially alleviate the degeneration of skeletal muscle in the acute stage after tendon rupture.

Keywords:  Acute phase; Fibro-adipogenic progenitors; Skeletal muscle degeneration; Tendon rupture; Tibialis anterior tenotomy

DOI:  https://doi.org/10.4252/wjsc.v17.i6.105491
Brain Dev. 2025 Jul 01. pii: S0387-7604(25)00070-1. [Epub ahead of print]47(4): 104388

L-NAME improves the morphology and necrosis of skeletal muscle by activating PINK1-PARKIN mediated mitophagy in mdx mice.

Junxia Li, Wenjuan Wu, Guang Ji, Hui Dong, Hongran Wu, Xueqin Song.

   BACKGROUND: This study investigates mitophagy in Duchenne muscular dystrophy (DMD, OMIM #310200), focusing on how nitric oxide synthase (NOS) inhibition improves muscle tissue pathology by affecting mitophagy, which is implicated in muscle weakness due to dystrophin deficiency and may affect DMD-related cardiomyopathy and respiratory problems.
METHODS: Histopathological analysis, immunofluorescence staining, Western blot were used to study the mitophagy status of the tibialis anterior muscle in mdx mice without treatment or mdx mice administered L-NAME (L-NG-nitro arginine methylester), an inhibitor of NOS. For in vitro experiment, the effect of S-nitrosylation enzyme, N6022, on mitophagy in C2C12 cells was assessed using TEM (transmission electron microscopy), and Western blot.
RESULTS: Mdx mice showed dystrophic muscle pathology and elevated LC3 (microtubule-mssociated protein 1 light chain) and VDAC (voltage-dependent anion channel) expression, indicating increased mitophagy. Reduced PINK1 (PTEN-induced putative kinase 1) and PARKIN (E3 ubiquitin ligase PARK2) levels suggested incomplete mitochondrial clearance. L-NAME treatment improved muscle morphology and reduced necrosis, partially restoring mitophagy by increasing LC3 without matching VDAC upregulation. However, PINK1 and PARKIN were further reduced, suggesting mitophagic inefficiency. In C2C12 cells, GSNOR(S-nitrosoglutathione reductase) inhibition via N6022 elevated nitrosylation, impaired mitophagy, and caused mitochondrial accumulation with increased PINK1 but unchanged PARKIN, highlighting a critical role of nitrosylation balance in mitophagy regulation.
CONCLUSIONS: NOS inhibition may serve as a key point for further research on the progression of DMD disease and as a potential therapeutic target for this incurable disease.

Keywords:  Duchenne muscular dystrophy; GSNOR; L-NAME; Mitophagy; PINK1-PARKIN pathway; S-nitrosylation

DOI:  https://doi.org/10.1016/j.braindev.2025.104388
In Vitro Cell Dev Biol Anim. 2025 Jun 30.

Grb2/Sos1 signaling regulates the number of reserve cells in C2C12 cell culture.

Yosuke Nagata, Hiroto Iitsuka, Tomoharu Hagiwara.

  Skeletal muscle regeneration depends on satellite cells that maintain tissue homeostasis through self-renewal and the production of myoblasts that differentiate into mature myofibers. Dysregulation of these processes can lead to muscle degeneration, highlighting the need to elucidate their molecular mechanisms. In this study, we investigated the role of the Grb2/Sos1 signaling pathway in regulating satellite cell self-renewal and differentiation using C2C12 cells. Knockdown of either Grb2 or Sos1 significantly reduced the formation of Bcl-2-positive reserve cells and increased the proportion of differentiated myotubes. Conversely, forced expression of Grb2 increased the number of reserve cells, whereas the Grb2 P49L mutant, which disrupts its interaction with Sos1, decreased reserve cell formation and resulted in thinner myotubes. Although forced expression of Sos1 alone did not significantly increase reserve cell numbers, the chimeric protein cSos-SH2, which combines elements of Grb2 and Sos1, produced a pronounced increase of reserve cells. These results demonstrate that a precise balance between Grb2 and Sos1, along with their coordinated subcellular localization, is critical for controlling reserve cell populations. Activated by growth factor receptor tyrosine kinases and extracellular matrix/integrin interactions, the Grb2/Sos1 signaling pathway is critical for maintaining the muscle satellite cell pool, thereby playing an essential role in muscle regeneration.

Keywords:  Grb2; Muscle satellite cells; Reserve cells; Skeletal muscle regeneration; Sos1

DOI:  https://doi.org/10.1007/s11626-025-01071-w
Clin Sci (Lond). 2025 Jul 01. pii: CS20255458. [Epub ahead of print]139(13):

Evaluating skeletal muscle wasting and weakness in models of critical illness.

Amy J Bongetti, Marissa K Caldow, Yasmine Ali Abdelhamid, Gordon S Lynch.

  Skeletal muscle wasting and weakness are common complications associated with admission to the intensive care unit (ICU), with the loss of muscle mass and function increasing mortality and contributing to physical impairments post-discharge. While our understanding of the pathophysiology of this condition, commonly termed 'ICU-acquired weakness' (ICU-AW), has advanced considerably, no effective therapies are available. ICU-AW broadly encompasses a range of muscle-related impairments in this setting, including, but not limited to, critical illness myopathy and sepsis-induced myopathy. Pre-clinical models of critical illness can provide insights into the mechanisms underlying muscle wasting and weakness. Cell culture systems can provide mechanistic interrogation, by isolating effects to skeletal muscle directly. Small animal models, like rats and mice, allow for mechanistic investigation of ICU-AW using genetic models and testing pharmacological interventions. Larger animal models, including pigs and sheep, facilitate repeated blood and tissue sampling and can more closely recapitulate the standard-of-care within ICU settings. Although animal models can be advantageous for scientific investigation, they also have important limitations. Barriers to developing effective interventions include difficulty in obtaining muscle biopsies from patients, translating experimental findings between animal models and humans and replicating aspects of different ICU settings. This review explores the advantages and shortcomings of different pre-clinical models of critical illness, identifies gaps in understanding muscle wasting and weakness in critical illness and provides recommendations for improving the translation of therapeutics to promote functional recovery for patients post-discharge.

Keywords:  animal models; cell models; critical illness; inflammation; muscle wasting; muscle weakness; sepsis; skeletal muscle

DOI:  https://doi.org/10.1042/CS20255458
Sci Rep. 2025 Jul 01. 15(1): 20527

PGC-1 alpha overexpression in the skeletal muscle results in a metabolically active microbiome which is independent of redox signaling.

Erika Koltai, Soroosh Mozaffaritabar, Lei Zhou, Attila Kolonics, Atsuko Koike, Kumpei Tanisawa, Jonguk Park, Ferenc Torma, Zsolt Radak.

  In this study, we investigated the potential relationship between the mitochondrial network and the microbiome using wild-type and skeletal muscle-specific PGC-1α (Pparg coactivator 1 alpha) overexpressing mice, both with and without exercise training. Basal PGC-1α levels were significantly higher in the skeletal muscle (J Physiol Biochem 80:329-335, 2024. https://doi.org/10.1007/s13105-024-01006-1 ) and, notably, in the colon, which is anatomically proximal to the microbiome. However, no significant changes were observed in cell signaling or mitochondria-related proteins within the colon. On the other hand, mitochondrial H₂O₂ production in the colon decreased in the PGC-1α overexpressing group. The relative abundance of several bacterial taxa differed between wild-type and PGC-1α overexpressing groups at baseline condition, indicating a shift in the microbiome milieu probably to cope with the increased metabolism, enhanced short-chain fatty acid utilization, and improved endurance capacity. Ten weeks of exercise training differentially modulated the host microbiome in PGC-1α overexpressing and wild-type mice, facilitating adaptations to a broad range of exercise-induced challenges. The results of this study provide new insights into the possible cross-talk between mitochondria and the microbiome.

Keywords:  Host–microbial interaction; Microbiota; Mitochondria; PGC-1α; Physical exercise

DOI:  https://doi.org/10.1038/s41598-025-05594-w
Regen Biomater. 2025 ;12 rbaf050

Advancements in skeletal muscle tissue engineering: strategies for repair and regeneration of skeletal muscle beyond self-repair.

Lei Qi, Fengyuan Zhang, Kexin Wang, Bingqian Chen, Xia Li, Jin Xu, Jiacheng Sun, Boya Liu, Zihui Gao, Yanan Ji, Leilei Gong, Youhua Wang, Xinlei Yao, Xiaosong Gu, Hualin Sun.

  Skeletal muscle is a vital organ of exercise and energy metabolism, playing a crucial role in maintaining body posture, enabling movement and supporting overall health. When skeletal muscle undergoes minor injuries, it has the inherent ability to self-repair and regain function. However, the ability of skeletal muscle self-repair is affected in severe muscle damage, resulting in significant muscle loss and functional impairments. For the severe muscle injury, tissue engineering strategies are used as the new methods to promote the repair and regeneration of skeletal muscle. Skeletal muscle tissue engineering (SMTE) aims to repair or regenerate skeletal muscle using seed cells, scaffolds, bioactive molecules or their combinations to reverse muscle loss caused by traumatic injury or congenital muscle defects. In this study, we provide an overview of the structure and contraction process of skeletal muscle, as well as its mechanisms of natural repair and regeneration. We describe the seed cells with myogenic potential and show natural, synthetic and composite biomaterials, as well as advanced technologies for manufacturing scaffolds used in SMTE. SMTE has broad prospects, but it still faces many challenges before clinical application. The continued advancement of muscle tissue engineering will yield innovative outcomes with significant clinical potential for skeletal muscle regeneration.

Keywords:  advanced techniques; biomaterials; seed cells; skeletal muscle tissue engineering

DOI:  https://doi.org/10.1093/rb/rbaf050
Int J Biol Macromol. 2025 Jun 30. pii: S0141-8130(25)06200-2. [Epub ahead of print]319(Pt 4): 145645

Injectable borax-loaded alginate hydrogels reduce muscle atrophy, modulate inflammation, and promote neuroprotection in the SOD1G93A mouse model of ALS through mechanisms involving IGF-Akt-mTOR signaling.

Ana Rodriguez-Romano, Juan Gonzalez-Valdivieso, Laura Moreno-Martinez, Juan Francisco Vázquez Costa, Rosario Osta, Patricia Rico.

  Amyotrophic Lateral Sclerosis (ALS) is a prevalent condition characterized by motor neuron loss and skeletal muscle paralysis. Despite being associated to mutations in over 40 genes, its etiology remains elusive without a cure or effective treatment. ALS, historically considered a motor neuron disease, is defined today as a multisystem disorder involving non-neuronal cell types, including early muscle pathology independent of motor neuron degeneration (dying back hypothesis), thus skeletal muscle actively contributes to disease pathology, making it a viable therapeutic target for ALS. Our previous research has shown that boron transporter NaBC1 (encoded by the SLC4A11 gene), after activation co-localizes with integrins and growth factor receptors synergistically enhancing muscle repair. Here we investigate the effects of injectable alginate-based hydrogels for controlled local borax release in Amyotrophic Lateral Sclerosis muscle. Treated mice showed improved motor function, prolonged survival, and activation of essential muscle metabolic pathways, leading to enhanced muscle repair and reduced atrophy and inflammation. Interestingly, local muscle repair activation provided retrograde neuroprotection by preserving motor neurons and reducing neuro-inflammation. This study highlights the role of muscle tissue in ALS pathology, supporting its targeting with NaBC1-based therapies for muscle regeneration.

Keywords:  ALS; Alginate hydrogel; Borax; Muscle regeneration; NaBC1 transporter (SLC4A11)

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145645
medRxiv. 2025 Jun 12. pii: 2025.06.12.25329490. [Epub ahead of print]

Striatal Dopamine and Skeletal Muscle Energy Metabolism in Older Adults.

Caterina Rosano, Nico I Bohnen, Brian LoPresti, Lana M Chahine, Haley N Barnes, Stephanie L Studenski, Nancy W Glynn, Anne B Newman, David J Marcinek, Russell T Hepple, Paul Coen.

Dopamine (DA) in the central nervous system is considered a master regulator of mobility performance and vigor, but its mechanistic relationship with skeletal muscle energetics is unclear. We tested the cross-sectional association of striatal DA and skeletal muscle mitochondrial function in 146 older adults participating in the Study of Muscle, Mobility and Aging (75.4 years old, 54% women). Striatal DA was measured using (+)-a-[11C] dihydrotetrabenazine (DTBZ) PET imaging for the limbic, sensorimotor, and executive control subregions. Mitochondrial capacity to produce ATP (ATPmax, mM ATP/s) was measured in vivo using 31P magnetic resonance spectroscopy after repeated voluntary muscle contractions. Ex-vivo respirometry assays from biopsies of resting muscle captured complementary aspects of mitochondrial function under optimal conditions. In multivariable linear regression models, [11C]DTBZ in the limbic striatum, but not other subregions, was positively associated with greater ATPmax in vivo, independent of demographics, muscle volume, leg power, white matter hyperintensities, gray matter atrophy, moderate-to-vigorous physical activity and diabetes (β = 0.275, standard error 0.108, p=0.019). [11C]DTBZ was not associated with the ex-vivo mitochondrial respiration markers (p>0.2). The role of striatal limbic DA and the energetic capacity of skeletal muscles should be further investigated in older adults.

DOI: https://doi.org/10.1101/2025.06.12.25329490
Adv Sci (Weinh). 2025 Jul 02. e04064

Pancreatic Cancer-Derived Extracellular Vesicles Enriched with miR-223-5p Promote Skeletal Muscle Wasting Associated with Cachexia.

Kangjing Xu, Rongxi Shen, Li Zhang, Xuejin Gao, Xinbo Wang, Changhua Zhang, Xi Chen, Xinying Wang.

  Pancreatic ductal adenocarcinoma (PDAC) with cachexia-related muscle wasting as the main manifestation is associated with poor overall survival. Extracellular vesicles (EVs) are key mediators of inter-organ communication. Here, EVs and EV-microRNAs (miRNAs) are identified as mediate PDAC-skeletal muscle communication. EVs are isolated from PDAC patients, mouse models, patients-derived organoids, and mouse pancreatic cancer cells. Plasma-derived EVs from PDAC patients or mice are observed to remarkably induced muscle wasting in vitro and in vivo. Depletion of miRNA cargo in these EVs significantly alleviates their detrimental effects on skeletal muscles. Deep RNA sequencing is conducted to profile differentially expressed miRNAs in plasma EVs from patients with or without PDAC. The findings reveal that the expression of miR-223-5p expression in PDAC patients' plasma EVs is negatively associated with the 3-year overall survival. Mechanistic studies show that miR-223-5p contributes to reduced METTL14 transcription by targeting MAFA, associated with decreased m6A methylation in skeletal muscles and muscle wasting. This study highlights the absorption of miRNA in PDAC-derived EVs by skeletal muscles and reveals a previously unrecognized function of PDAC-derived EV-miR-223-5p in tumor-muscle inter-organ communication, offering novel insight into EV-miR-223-5p-based diagnostic and therapeutic strategies for PDAC patients with sarcopenia upon further validation.

Keywords:  cancer cachexia; extracellular vesicles; miR‐223‐5p; muscle wasting; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1002/advs.202504064
Diabet Med. 2025 Jul 01. e70086

Dorothy Hodgkin lecture 2024: Insulin regulation of mitochondrial biogenesis and function-Impact of dysregulation of mitochondrial function in diabetes and its complications.

K Sreekumaran Nair.

  Skeletal muscle atrophy was a characteristic of type 1 diabetes (T1DM) prior to insulin discovery and replacement. Indirect calorimetry during the post-absorptive state demonstrated that increased fuel oxidation during transient insulin deprivation in T1DM caused depletion of energy stores. Further, insulin has a critical role in preserving muscle mitochondrial content and function by enhancing mitochondrial biogenesis and proteostasis. Insulin deficiency not only inhibits mitochondrial biogenesis but also accelerates the degradation of mitochondrial proteins, causing a decline in mitochondrial content and efficiency. Inefficient mitochondrial respiration, reflected by the uncoupling of oxidative phosphorylation and consequent decline in ATP production, adversely affects many cellular functions and causes high oxidative stress. Oxidative stress adversely affects cardiovascular functions and damages many skeletal muscle proteins, accelerating their degradation and explaining muscle atrophy. Increased degradation of muscle proteins increases amino acid efflux that stimulates the liver to synthesize many non-insulin-dependent proteins, potentially contributing to macrovascular complications. This phenomenon explains a paradoxical increase in whole-body protein synthesis during insulin deficiency. Further, the mitochondrial biology of brain regions rich in insulin receptors concurrent with accelerated transport of ketones and lactate across the blood-brain barrier during insulin deficiency seems to protect the brain from oxidative stress. In contrast, insulin resistance associated with less ketone and lactate production renders the brain susceptible to protein oxidative damage. Oxidative damage and reduced ATP production potentially explain the higher prevalence of dementia in insulin-resistant people. Enhancement of insulin sensitivity by aerobic exercise and metformin in pre-clinical studies prevents mitochondrial dysfunction and oxidative damage to the brain.

Keywords:  ATP; dementia; diabetes; insulin; mitochondria; muscle atrophy; oxidative stress

DOI:  https://doi.org/10.1111/dme.70086
Res Sq. 2025 Jun 12. pii: rs.3.rs-6701121. [Epub ahead of print]

Decoding Cellular Communication Networks and Signaling Pathways in Bone, Skeletal Muscle, and Bone-Muscle Crosstalk Through Spatial Transcriptomics.

Hong-Wen Deng, Chuan Qiu, Yisu Li, Yun Gong, Weiqiang Lin, Boluwatife Afolabi, Vivek Thumbigere-Math, Kuan-Jui Su, Jeffrey Deng, Shashank Sajjan Mungasavalli Gnanesh, Zhe Luo, Qing Tian, Yiping Chen, Hui Shen.

Bone and skeletal muscle are essential components of the musculoskeletal system, enabling movement, load-bearing, and systemic regulation. These tissues communicate through dynamic bone-muscle crosstalk mediated by cytokines, growth factors, and extracellular matrix (ECM) proteins. The spatial organization of these mediators is critical to maintaining tissue integrity, and disruptions contribute to diseases such as osteoporosis, sarcopenia, and metabolic syndrome. Despite the importance of spatial context, studies using spatial transcriptomics (ST) to investigate bone-muscle interactions remain limited. Here, we applied 10X Genomics Visium ST profiling and advanced computational tools to characterize cell-cell communication networks and ligand-receptor (L-R) interactions in mouse femur and adjacent skeletal muscle. We identified eight major cell types: erythroid cells, endothelial cells, skeletal muscle cells, osteoblasts, myeloid cells, monocytes/macrophages, mesenchymal stem cells, and adipocytes, each exhibiting distinct spatial gene expression profiles. Signaling pathway analysis revealed 13 key pathways mediating intra- and inter-tissue communication, including COLLAGEN, THBS, VEGF, FN1, and TENASCIN. Notable L-R pairs involved in bone, muscle, and bone-muscle crosstalk include Col1a2-Sdc4 (osteoblast-ECM interactions), Tnxb-Sdc4 (muscle-to-endothelial signaling), Vegfa-Vegfr1 and Vegfa-Vegfr2 (muscle-to-endothelial/myeloid signaling), and Comp-Sdc4 (monocyte/macrophage-to-osteoblast signaling). This study presents the first spatially resolved map of cell-cell communication across bone and skeletal muscle, providing novel insights into their molecular crosstalk. These findings offer a critical foundation for future therapeutic strategies targeting musculoskeletal disorders.

DOI: https://doi.org/10.21203/rs.3.rs-6701121/v1
Sci Rep. 2025 Jul 04. 15(1): 23946

Muscle spindle afferent neurons preferentially degenerate with aging.

Minako Kawai-Takaishi, Tohru Hosoyama.

  Muscle spindles sense changes in muscle length and transmit them to the central nervous system. Proprioception is essential for gait and postural maintenance, the abnormality of which has been linked to gait disorders and the risk of falling in older adults. However, the effects of aging on the muscle spindle structure remain nebulous. This study investigated age-related structural changes in the muscle spindles (from the equator to the polar) in the soleus and extensor digitorum longus (EDL) muscles of young, middle-aged, and aged mice. The findings indicated that the shape of the annulospiral endings of the sensory neurons began to deteriorate in middle-aged compared with young mice and was further exacerbated in aged mice. These changes were particularly pronounced in the nuclear bag fibers, whereas no significant age-related changes were observed in the intrafusal fibers or capsules. A decline in gait function due to changes in weight-bearing and weight-shifting in aged mice was also observed, suggesting that the deterioration of proprioceptive sensory neurons that innervate the nuclear bag fiber responsible for dynamic sensitivity prevents proper coordinated movement and contributes to movement disorders in aged animals including humans, together with the functional decline of extrafusal fibers.

Keywords:  Aging; Annulospiral ending; Intrafusal fibers; Movement disorders; Muscle spindle; Proprioceptive sensory neuron

DOI:  https://doi.org/10.1038/s41598-025-08270-1
J Clin Invest. 2025 Jul 01. pii: e181881. [Epub ahead of print]

Iron supplementation alleviates pathologies in a mouse model of facioscapulohumeral muscular dystrophy.

Kodai Nakamura, Huascar-Pedro Ortuste-Quiroga, Naoki Horii, Shin Fujimaki, Toshiro Moroishi, Keiichi I Nakayama, Shinjiro Hino, Yoshihiko Saito, Ichizo Nishino, Yusuke Ono.

  Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disease caused by ectopic expression of the toxic protein DUX4, resulting in muscle weakness. However, the mechanism by which DUX4 exerts its toxicity remains unclear. In this study, we observed abnormal iron accumulation in muscles of patients with FSHD and in muscle-specific DUX4-expressing (DUX4-Tg) mice. Treatment with iron chelators, an iron-deficient diet, and genetic modifications inhibiting intracellular uptake of iron did not improve but rather exacerbated FSHD pathology in DUX4-Tg mice. Unexpectedly, however, iron supplementation, either from a high-iron diet or intravenous iron administration, resulted in remarkable improvement in grip strength and running performance in DUX4-Tg mice. Iron supplementation suppressed abnormal iron accumulation and the ferroptosis-related pathway involving increased lipid peroxidation in DUX4-Tg muscle. Muscle-specific DUX4 expression led to retinal vasculopathy, a part of FSHD pathology, which was prevented by iron administration. Furthermore, high-throughput compound screening of the ferroptosis pathway identified drug candidates including Ferrostatin-1 (Fer-1), a potent inhibitor of lipid peroxidation. Treatment with Fer-1 dramatically improved physical function in DUX4-Tg mice. Our findings demonstrate that DUX4-provoked toxicity is involved in the activation of the ferroptosis-related pathway and that supplementary iron could be a promising and readily available therapeutic option for FSHD.

Keywords:  Metabolism; Muscle; Muscle biology; Neuromuscular disease; Skeletal muscle

DOI:  https://doi.org/10.1172/JCI181881
Nat Aging. 2025 Jun 30.

Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis.

Roméo S Blanc, Nidhi Shah, Sarah Hachmer, Noah A S Salama, Fanju W Meng, Alireza Mousaei, Gayatri Puri, Jeonghye Hannah Hwang, Elizabeth E Wacker, Benjamin A Yang, Carlos A Aguilar, Joe V Chakkalakal, John O Onukwufor, Patrick J Murphy, Laura M Calvi, F Jeffrey Dilworth, Robert T Dirksen.

Aging is characterized by a decline in the functionality and number of stem cells across the organism. In this study, we uncovered a mechanism by which systemic inflammation drives muscle stem cell (MuSC) aging through epigenetic erosion. We demonstrate that age-related inflammation decreases monomethylation of H4K20 in MuSCs, disrupting their quiescence and inducing ferroptosis, a form of iron-dependent cell death. Our findings show that inflammatory signals downregulate Kmt5a, the enzyme responsible for depositing H4K20me1, leading to the epigenetic silencing of anti-ferroptosis genes. This results in aberrant iron metabolism, increased reactive oxygen species levels and lipid peroxidation in aged MuSCs. Notably, long-term inhibition of systemic inflammation that is initiated at 12 months of age effectively prevents ferroptosis, preserves MuSC numbers and enhances muscle regeneration and functional recovery. These findings reveal an epigenetic switch that links chronic inflammation to MuSC aging and ferroptosis, offering potential therapeutic strategies for combating age-related muscle degeneration.

DOI: https://doi.org/10.1038/s43587-025-00902-5
Sci Rep. 2025 Jul 03. 15(1): 23692

Effect of transforming growth factor beta receptor I inhibitors on myotube formation in vitro.

Louise De Saeytyd, Zhihao Wang, Marjon Bloemen, Johannes W Von den Hoff.

  Skeletal muscle injury often occurs after trauma or reconstructive surgery. However, full muscle regeneration is often not achieved because of fibrosis. A key pathway in fibrosis is transforming growth factor ß (TGFß) signaling. Many small molecules that inhibit the TGFß receptor are investigated for their anti-fibrotic activity. However, their effects on myofiber formation are unknown. The aim of this study was to investigate the effect of five transforming growth factor-beta receptor I (TGFßRI) inhibitors on myotube formation in vitro; galunisertib, SM16, AZ12799734, SB431542 and IN1130. First, the toxicity of the inhibitors on C2C12 myoblasts was determined (0-100 µM) as well as their effects on proliferation. Next, the inhibitors (0-20µM) were added to C2C12 cell cultures to determine their effect on myotube formation. Immunofluorescence staining for myosin heavy chain was used to identify myotubes. Data analysis and statistics were performed with Graphpad Prism software. In contrast to galunisertib, AZ12799734 and SB431542, SM16 and IN1130 had no toxic effects. Galunisertib and AZ12799734 were toxic from 10 µM on (p < 0.05) and SB431542 only at 100 µM (p < 0.05). All inhibitors reduced proliferation already at 1 mM. SM16 and IN1130 reduced the fusion index at 1 µM and higher (p < 0.05). SB431542 reduced the fusion index at 5 µM and higher (p < 0.05), and AZ12799734 at 10 µM (p < 0.05) and higher. Only galunisertib had no effect on the fusion index. These results show that galunisertib does not impair the formation of myotubes from C2C12 myoblasts and might be suitable as an anti-fibrotic therapy for muscle regeneration.

Keywords:  ALK5 inhibitors; Galunisertib; Myoblast; Myotube; Small molecule inhibitor; Transforming growth factor beta (TGF-β)

DOI:  https://doi.org/10.1038/s41598-025-09381-5
Cell Metab. 2025 Jul 01. pii: S1550-4131(25)00296-7. [Epub ahead of print]37(7): 1455-1456

Muscle needs NAD, but how much?

David W Frederick, Joseph P McGaunn, Joseph A Baur.

Supplements that increase nicotinamide adenine dinucleotide (NAD) have become increasingly popular, and much of the attention has focused on potential benefits to skeletal muscle. In this issue of Cell Metabolism, Chubanava et al.1 use an inducible model to lower NAD concentration in the muscles of adult mice, revealing a surprising lack of functional consequences.

DOI: https://doi.org/10.1016/j.cmet.2025.06.001
Int J Biol Sci. 2025 ;21(9): 3934-3948

WNT5B regulates myogenesis and fiber type conversion by affecting mRNA stability.

Danyang Fan, Yilong Yao, Chao Yan, Fanqinyu Li, Yalan Yang, Bingkun Xie, Zhonglin Tang.

  The wingless-integrated (WNT) signaling pathway is known to play a critical role in myogenesis. WNT5B, a member of the WNT family, is essential for determining cell fate and development. However, the molecular mechanisms by which WNT5B regulates myogenesis remain unclear. This study observed that WNT5B, which is conserved between mice and pigs, is highly expressed in the skeletal muscle. The expression of WNT5B was varied in the skeletal muscle between the Tongcheng (obese-type) and Landrace (lean-type) pigs. In vitro, WNT5B promoted skeletal muscle cell proliferation and cell cycle progression, while inhibited cell apoptosis. In vivo, WNT5B promoted myofiber thickness and increased slow-type muscle fibers in porcine skeletal muscles. Mechanically, a SNP site (c.1608 A > G) located in the 3' untranslated region (3'UTR) of WNT5B regulated transcript attenuation and acts through AU-rich element mediation (ARE) to influence myogenesis. Also, the SNP was located in the miRNA response element of miR-29a/b/c to influence WNT5B expression. However, ARE sites did not affect the binding relationship of miR-29a/b/c. In conclusion, this study demonstrated that the SNP (c.1608 A > G) affects WNT5B mRNA stability by protecting the 3'UTR of the WNT5B from the degrading effects of miR-29a/b/c. This study reveals the critical role of WNT5B in myogenesis and indicates that it is a novel candidate gene for pig breeding.

Keywords:  WNT5B; fiber type conversion; mRNA stability; myogenesis; single nucleotide polymorphisms

DOI:  https://doi.org/10.7150/ijbs.102309
J Muscle Res Cell Motil. 2025 Jul 03.

The impact of mitokine MOTS-c administration on the soleus muscle of rats subjected to a 7-day hindlimb suspension.

Daria A Sidorenko, Irina D Lvova, Sergey A Tyganov, Boris S Shenkman, Kristina A Sharlo.

  The aim of the study was to investigate the effect of MOTS-c on the key functional alterations in the rat soleus muscle during 7-day unloading - the transformation of slow fibers into fast ones, atrophy and increased fatigue. We daily intraperitoneally injected male Wistar rats with a short mitochondrial peptide MOTS-c during 7-day unloading of their hind limbs. After the end of the experiment, we conducted an ex vivo fatigue test of soleus muscle and showed that the MOTS-c administration prevents increased fatigue during 7-day hind limb unloading. Also, using immunohistochemical analysis, we showed that MOTS-c prevents the transformation of slow fibers into fast ones, mitigates the slow muscle atrophy fibers (but not fast ones) of the soleus muscle. In the group receiving MOTS-c, the decrease in Akt and GSK3β phosphorylation was prevented, and the 18 S and 28 S rRNA levels were at the control level. The ubiquitin ligases MuRF and Atrogin-1 mRNA were also reduced compared to the hindlimb unloading group with placebo. In addition, MOTS-c prevented a decrease in the expression of a few mitochondrial biogenesis parameters and the level of ACC phosphorylation (AMPK target). Thus, the MOTS-C injections during hind limb unloading lead to the normalization of several protein synthesis and degradation processes and support the expression of genes that ensure muscle resistance to fatigue.

Keywords:  Disuse; Hindlimb unloading; MOTS-c; Muscle atrophy; Postural muscles

DOI:  https://doi.org/10.1007/s10974-025-09700-3
Nat Commun. 2025 Jul 01. 16(1): 5976

Molecular mechanism of Activin receptor inhibition by DLK1.

Daniel Antfolk, Qianqian Ming, Anna Manturova, Erich J Goebel, Thomas B Thompson, Vincent C Luca.

Delta-like non-canonical Notch ligand 1 (DLK1) influences myogenesis, adipogenesis, and other aspects of human development through a process that is largely attributed to the downregulation of Notch signaling. Here, we show that DLK1 does not bind to Notch receptors or affect ligand-mediated Notch activation, but instead engages the TGF-β superfamily member Activin receptor type 2B (ACVR2B). The crystal structure of the DLK1-ACVR2B complex reveals that DLK1 mimics the binding mode of canonical TGF-β ligands to compete for access to ACVR2B. In functional assays, DLK1 antagonizes Myostatin-ACVR2B signaling to promote myoblast differentiation, rationalizing a mechanism for the role of DLK1 in muscle development and regeneration. Crosstalk between Notch and TGF-β is mediated by interactions between the transcriptional regulators SMAD2/3 and the Notch intracellular domain (NICD), and DLK1 inhibits SMAD2/3-NICD colocalization. These findings indicate that DLK1 acts directly on ACVR2B to inhibit signaling, whereas the observed effects on Notch may be an indirect result of DLK1 interference with NICD-SMAD complex formation.

DOI: https://doi.org/10.1038/s41467-025-60634-3
Mol Cell Biochem. 2025 Jun 30.

A review: oxidative stress in skeletal muscle and the non-coding RNAs behind it.

Dongdong Bo, Jiameng Shen, Yilin Bai, Jing Li, Yuanyuan Wang, Ziqi Li, Zerui You, Anran Gai, Qing Zhang, Yueyu Bai.

  Oxidative damage, primarily caused by reactive oxygen species (ROS), leads to the oxidation of cellular components, particularly in skeletal muscles. ROS accumulation in muscle fibers results in the oxidation of proteins, lipids, and nucleic acids, affecting the stability of muscle structure and function. Signaling pathways, including NF-κB, MAPK, Nrf2-ARE, PI3K-AKT, and p53 pathways, are intimately associated with oxidative stress. Understanding the impact of oxidative stress on skeletal muscles and the regulatory mechanisms of ncRNA on skeletal muscle oxidative stress is crucial for preventing muscle damage caused by oxidative stress. Oxidative stress mechanisms in skeletal muscles are intricate, and involve many regulatory factors and signaling pathways. NcRNAs play critical regulatory roles in these responses, but their specific functions and mechanisms require further research. Future research should explore in depth the interactions between ncRNAs and other molecules, providing new theoretical foundations and practical guidance for the prevention of muscle oxidative stress. This review summarizes current understanding of molecular mechanisms driving oxidative stress in skeletal muscle, with emphasis on regulatory networks mediated by ncRNAs. Future investigations should focus on multi-omics integration of ncRNA crosstalk with redox signaling pathways, potentially informing preventive strategies against muscle dysfunction in metabolic and aging-related conditions.

Keywords:  Antioxidant; Muscle cell; Non-coding RNA; Oxidative stress; Skeletal muscle

DOI:  https://doi.org/10.1007/s11010-025-05339-3