bims-moremu 2025-07-27 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–07–27
37 papers selected by
Anna Vainshtein, Craft Science Inc.

Immune aging impairs muscle regeneration via macrophage-derived anti-oxidant selenoprotein P.
Metformin Suppresses the Mitochondrial and Transcriptional Response to Exercise Revealing a Conserved BCL6B Associated Angiogenic Program.
Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer.
MicroRNA-33 inhibition ameliorates muscular dystrophy by enhancing skeletal muscle regeneration.
Targeting ALDH2 to promote skeletal muscle health: A novel strategy against mitochondrial dysfunction.
Suppression of USP2 in mouse skeletal muscle: a model of oxidative stress in muscle tissue.
Cardiac, skeletal muscle and neuromuscular plasticity in disuse and inactivity.
Aerobic Exercise Delays Age-Related Sarcopenia in Mice via Alleviating Imbalance in Mitochondrial Quality Control.
Rapamycin Does Not Compromise Exercise-Induced Muscular Adaptations in Female Mice.
Impact of Acute Endurance Exercise on Alternative Splicing in Skeletal Muscle.
Circular RNA circAtxn10 regulates skeletal muscle cell differentiation by targeting miR-143-3p and Chrna1.
Making Sense of MYC in Skeletal Muscle: Location, Duration, and Magnitude.
Tissue-engineered neuromuscular organoids.
Transcriptional Signatures of Aerobic Exercise-Induced Muscle Adaptations in Humans.
The m6A reader IGF2BP3 facilitates myogenesis by activating the CAMK2B-MEF2C axis.
Unraveling the role of STAT3 in Cancer Cachexia: pathogenic mechanisms and therapeutic opportunities.
In vivo evaluation of decellularized skeletal muscle matrices for skeletal muscle repair: A systematic review.
Physiological processes induced by different types of physical activity that either oppose or enhance postprandial glucose tolerance.
The endocannabinoid system & malignant hyperthermia: From molecular signaling towards clinical implications.
Gene therapy ameliorates neuromuscular pathology in CLN3 disease.
Calsequestrin-1 Deficiency Induced Malignant Hyperthermia-Like Skeletal Injury through Mitochondrial Disorder.
Alcohol mediated skeletal muscle adaptations and their impact on comorbidities.
Impact of myokines on chronic liver diseases: exploring the effects of metabolic dysfunction-associated steatotic liver disease (MASLD) on skeletal muscle. A narrative review.
PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease.
Protocol for investigating chromatin architecture in adult skeletal muscle stem cells using high-throughput chromosome conformation capture.
Effects of Aerobic Exercise on Irisin and Skeletal Muscle Autophagy in ApoE-/- Mice.
Effect of sodium-glucose cotransporter-2 inhibitors on skeletal muscle.
Mechanisms of Exercise in Improving Sarcopenia.
Intracellular amyloidosis in peripheral nerve and skeletal muscle.
Targeting ERRs to counteract age-related muscle atrophy associated with physical inactivity: a pilot study.
State-of-the-art insights into myokines as biomarkers of sarcopenia: a literature review.
Advances in MicroRNAs in Pathophysiology of Duchenne Muscular Dystrophy.
Mechanisms of Muscle Atrophy in Type 2 Diabetes Mellitus: Factors Dysregulating Muscle Protein Synthesis and Breakdown.
Impact of polymorphisms on gene expression and splicing in response to exercise and diet-induced weight loss in human skeletal muscle tissues.
Molecular genetics of J-domain protein-related chaperonopathies in skeletal muscle.
Microtubules coordinate mitochondria transport with myofibril morphogenesis during muscle development.
The emerging role of multiomics in aging research.

EMBO Rep. 2025 Jul 18.

Immune aging impairs muscle regeneration via macrophage-derived anti-oxidant selenoprotein P.

Dieu-Huong Hoang, Jessica Bouvière, Johanna Galvis, Pauline Moullé, Orane Mercier, Eugenia Migliavacca, Ananga Ghosh, Gaëtan Juban, Sophie Liot, Pascal Stuelsatz, Fabien Le Grand, Jérôme N Feige, Rémi Mounier, Bénédicte Chazaud.

  Muscle regeneration is impaired with aging, due to both intrinsic defects of muscle stem cells (MuSCs) and alterations of their niche. Here, we monitor the cells constituting the MuSC niche over time in young and old regenerating mouse muscle. Aging alters the expansion of all niche cells, with prominent phenotypes in macrophages that show impaired resolution of inflammation. RNA sequencing of FACS-isolated mononucleated cells uncovers specific profiles and kinetics of genes and molecular pathways in old versus young muscle cells, indicating that each cell type responds to aging in a specific manner. Moreover, we show that macrophages have an altered expression of Selenoprotein P (Sepp1). Macrophage-specific deletion of Sepp1 is sufficient to impair the acquisition of their restorative profile and causes inefficient skeletal muscle regeneration. When transplanted in aged mice, bone marrow from young WT mice, but not Sepp1-KOs, restores muscle regeneration. This work provides a unique resource to study MuSC niche aging, reveals that niche cell aging is asynchronous and establishes the antioxidant Selenoprotein P as a driver of age-related decline of muscle regeneration.

Keywords:  Aging; Macrophages; Selenoprotein P; Skeletal Muscle Regeneration

DOI:  https://doi.org/10.1038/s44319-025-00516-3
J Appl Physiol (1985). 2025 Jul 22.

Metformin Suppresses the Mitochondrial and Transcriptional Response to Exercise Revealing a Conserved BCL6B Associated Angiogenic Program.

Matthew D Bruss, Christian James Elliehausen, Josef P Clark, Dennis M Minton, Adam R Konopka.

  We have previously demonstrated that the inhibitory effect of metformin on skeletal muscle mitochondrial respiration was associated with attenuated improvements in whole-body insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) in older adults. To identify processes associated with the inhibitory effect of metformin on mitochondrial adaptations to AET, we evaluated the skeletal muscle transcriptome, mitochondrial respiration, and hydrogen peroxide (H2O2) emissions in 7-month-old male C57BL6/J mice after 8-weeks of non-exercise sedentary control (SED) or progressive AET with and without metformin treatment. Similar to our findings in humans, metformin diminished the improvement in whole-body cardiometabolic adaptations and the increase in mitochondrial respiration in both isolated mitochondria and permeabilized muscle fibers after AET in mice. However, AET with or without metformin did not impact resting mitochondrial H2O2 emissions. Metformin decreased the number of differentially expressed genes after AET by ~50% and suppressed several transcription factors and signal transduction pathways involved in skeletal muscle proteostasis, myogenesis, oxidative capacity, and angiogenesis. A parallel analysis of human resistance exercise data revealed overlapping metformin-sensitive transcription factors and BCL6B-associated signaling networks implicated in angiogenesis, suggesting a conserved regulatory axis across species and exercise modalities. Collectively, these data demonstrate that attenuation of mitochondrial respiration by metformin coincides with transcriptional repression and identify specific pathways and regulators, such as BCL6B, that may contribute to the suppression of exercise adaptations by metformin.

Keywords:  BCL6B; PI3K-AKT-mTOR; angiogenesis; endurance exercise; respiration

DOI:  https://doi.org/10.1152/japplphysiol.00432.2025
Mol Metab. 2025 Jul 16. pii: S2212-8778(25)00118-8. [Epub ahead of print] 102211

Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer.

Luca J Delfinis, Shahrzad Khajehzadehshoushtar, Luke D Flewwelling, Nathaniel J Andrews, Madison C Garibotti, Shivam Gandhi, Aditya N Brahmbhatt, Brooke A Morris, Bianca Garlisi, Sylvia Lauks, Caroline Aitken, Leslie Ogilvie, Stavroula Tsitkanou, Jeremy A Simpson, Nicholas P Greene, Arthur J Cheng, Jim Petrik, Christopher G R Perry.

  Muscle loss with cancer causes weakness, worsens quality of life, and predicts reduced overall survival rates. Recently, muscle weakness was identified during early-stage cancer before atrophy develops. This discovery indicates that mechanisms independent of muscle loss must contribute to progressive weakness. While mitochondrial stress responses are associated with early-stage 'pre-cachexia' weakness, a causal relationship has not been established. Here, using a mouse model of metastatic ovarian cancer cachexia, we identified that the well-established mitochondrial-targeted plastoquinone SkQ1 partially prevents muscle weakness occurring before the development of atrophy in the diaphragm. Furthermore, SkQ1 improved force production during atrophy without preventing atrophy itself in the tibialis anterior and diaphragm. These findings indicate that atrophy-independent mechanisms of muscle weakness occur in different muscle types throughout ovarian cancer. Ovarian cancer reduced flexor digitorum brevis (FDB) whole muscle force production and myoplasmic free calcium ([Ca2+]i) during contraction in intact single muscle fibers, both of which were prevented by SkQ1. Remarkably, changes in mitochondrial reactive oxygen species and pyruvate metabolism were heterogeneous across time and between muscle types which highlights a considerable complexity in the relationships between mitochondria and muscle remodeling throughout ovarian cancer. These discoveries identify that muscle weakness can occur independent of atrophy throughout ovarian cancer in a manner that is linked to improved calcium handling. The findings also demonstrate that mitochondrial-targeted therapies exert a robust effect in preserving muscle force early during ovarian cancer during the pre-atrophy period and in late stages once cachexia has become severe.

Keywords:  Ovarian cancer cachexia; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1016/j.molmet.2025.102211
EMBO Mol Med. 2025 Jul 23.

MicroRNA-33 inhibition ameliorates muscular dystrophy by enhancing skeletal muscle regeneration.

Naoya Sowa, Takahiro Horie, Yuya Ide, Osamu Baba, Kengo Kora, Takeshi Yoshida, Yujiro Nakamura, Shigenobu Matsumura, Kazuki Matsushita, Miyako Imanaka, Fuquan Zou, Eitaro Kume, Hidenori Kojima, Qiuxian Qian, Kayo Kimura, Ryotaro Otsuka, Noriko Hara, Tomohiro Yamasaki, Chiharu Otani, Yuta Tsujisaka, Tomohide Takaya, Chika Nishimura, Dai Watanabe, Koji Hasegawa, Jun Kotera, Kozo Oka, Ryo Fujita, Akihiro Takemiya, Takashi Sasaki, Yuuya Kasahara, Satoshi Obika, Takeshi Kimura, Koh Ono.

  Muscular dystrophy is a group of diseases characterized by progressive weakness and degeneration of skeletal muscles, for which there is currently no cure. Here, we show that microRNA (miR)-33a/b play a crucial role in muscle regeneration. miR-33a was upregulated during myoblast differentiation and in skeletal muscles of mdx mice, a genetic model of Duchenne muscular dystrophy (DMD). miR-33a deficiency enhanced muscle regeneration response to cardiotoxin injury and attenuated muscle degeneration and fibrosis in mdx mice. Conversely, a humanized mouse model expressing miR-33a and miR-33b showed exacerbated muscle degeneration and fibrosis. Mechanistically, miR-33a/b inhibited satellite cell proliferation, leading to reduced muscle regeneration and increased fibrosis by targeting Cdk6, Fst, and Abca1. Local and systemic administration of anti-miRNA oligonucleotides targeting miR-33a/b ameliorated the dystrophic phenotype in mdx mice. Furthermore, miR-33b inhibition upregulated these target genes in myotubes differentiated from human induced pluripotent stem cells derived from a patient with DMD. These findings indicate that miR-33a/b are involved in muscle regeneration and their inhibition may represent a potential therapeutic strategy for muscular dystrophy.

Keywords:  Antisense Oligonucleotide; Muscular Dystrophy; Regeneration; microRNA-33a; microRNA-33b

DOI:  https://doi.org/10.1038/s44321-025-00273-9
J Physiol. 2025 Jul 20.

Targeting ALDH2 to promote skeletal muscle health: A novel strategy against mitochondrial dysfunction.

Katia S G Andrade, Jianming Liu, Dimitrius Santiago P S F Guimarães, Julio C B Ferreira, Zhigao Wang, Da-Zhi Wang, Leonardo R Silveira.

  The maintenance of skeletal muscle relies on several cellular signalling pathways directly linked to mitochondrial function. Mitochondria support skeletal muscle bioenergetics and are known as a primary source of reactive oxygen species (ROS). Indeed, mitochondrial dysfunction-induced excessive ROS accumulation leads to irreversible molecular damage caused by lipid peroxidation by product 4-hydroxy-trans-2-nonenal (4-HNE), this is able to directly inactivate proteins and DNA, causing mitochondrial and cellular dysfunction. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme responsible for counteracting this deleterious cycle by detoxifying aldehydes and converting them into less harmful molecules. In this context, ALDH2 is essential for functional skeletal muscle maintenance. In fact, studies published in the last decade show that ALDH2 overexpression downregulates atrophic genes; meanwhile, the lack of this protein is associated with muscle weakness and atrophy, demonstrating its relevance for maintaining muscle mass. In this context, interventions capable of increasing ALDH2 levels and/or activity are considered promising therapeutic strategies for mitigating oxidative damage, enhancing mitochondrial function, and preserving muscle integrity under adverse conditions.

Keywords:  aldehydic load; antioxidant; cachexia; sarcopenia; skeletal muscle; therapy

DOI:  https://doi.org/10.1113/JP288882
Exp Anim. 2025 Jul 19.

Suppression of USP2 in mouse skeletal muscle: a model of oxidative stress in muscle tissue.

Masaki Fujimoto, Tomohito Iwasaki, Marina Hosotani Saito, Naoki Takahashi, Mayuko Hashimoto, Eiki Takahashi, Hiroshi Kitamura.

  Emerging evidence indicates that oxidative stress in skeletal muscle is a prerequisite for sarcopenia in diabetic patients. In this study, we show that ubiquitin-specific protease (USP) 2 mitigates the accumulation of reactive oxygen species (ROS) in mature muscle cells. Treatment with ML364, a canonical USP2 inhibitor, robustly increased mitochondrial ROS in mouse C2C12 myotubes and caused an accompanying increase in the glutathione disulfide (GSSG)/glutathione (GSH) ratio. ML364 also caused mitochondrial damage in C2C12 myotubes, resulting in a reduction in intracellular adenosine triphosphate levels. Correspondingly, under diabetic condition, the muscle-specific Usp2-knockout (msUsp2KO) C57BL/6N mice exhibited a significantly higher lipid peroxide level and GSSG/GSH ratio in skeletal muscle than the control mice. The msUsp2KO mice also exhibited augmented insulin resistance and glucose intolerance, but showed no obvious deterioration in muscle weight or histology relative to the control mice. However, damaged mitochondria in the soleus muscle were more frequently observed in msUsp2KO mice than in the control mice. Together, these data suggest that USP2 mitigates ROS accumulation and subsequent mitochondrial damage in muscle cells in mice.

Keywords:  USP2; diabetes; oxidative stress; skeletal muscle

DOI:  https://doi.org/10.1538/expanim.25-0032
J Physiol. 2025 Jul 20.

Cardiac, skeletal muscle and neuromuscular plasticity in disuse and inactivity.

Paul L Greenhaff, Martino V Franchi, Kevin A Murach.

DOI: https://doi.org/10.1113/JP288890
Metabolites. 2025 Jul 11. pii: 472. [Epub ahead of print]15(7):

Aerobic Exercise Delays Age-Related Sarcopenia in Mice via Alleviating Imbalance in Mitochondrial Quality Control.

Danlin Zhu, Lian Wang, Haoyang Gao, Ze Wang, Ke Li, Xiaotong Ma, Linlin Zhao, Weihua Xiao.

  Background: Sarcopenia is a syndrome associated with aging, characterized by a progressive decline in skeletal muscle mass and function. Its onset compromises the health and longevity of older adults by increasing susceptibility to falls, fractures, and various comorbid conditions, thereby diminishing quality of life and capacity for independent living. Accumulating evidence indicates that moderate-intensity aerobic exercise is an effective strategy for promoting overall health in older adults and exerts a beneficial effect that mitigates age-related sarcopenia. However, the underlying molecular mechanisms through which exercise confers these protective effects remain incompletely understood. Methods: In this study, we established a naturally aging mouse model to investigate the effects of a 16-week treadmill-based aerobic exercise regimen on skeletal muscle physiology. Results: Results showed that aerobic exercise mitigated age-related declines in muscle mass and function, enhanced markers associated with protein synthesis, reduced oxidative stress, and modulated the expression of genes and proteins implicated in mitochondrial quality control. Notably, a single session of aerobic exercise acutely elevated circulating levels of β-hydroxybutyrate (β-HB) and upregulated the expression of BDH1, HCAR2, and PPARG in the skeletal muscle, suggesting a possible role of β-HB-related signaling in exercise-induced muscle adaptations. However, although these findings support the beneficial effects of aerobic exercise on skeletal muscle aging, further investigation is warranted to elucidate the causal relationships and to characterize the chronic signaling mechanisms involved. Conclusions: This study offers preliminary insights into how aerobic exercise may modulate mitochondrial quality control and β-HB-associated signaling pathways during aging.

Keywords:  Sarcopenia; aerobic exercise; mitochondrial quality control; skeletal muscle

DOI:  https://doi.org/10.3390/metabo15070472
Aging Cell. 2025 Jul 24. e70183

Rapamycin Does Not Compromise Exercise-Induced Muscular Adaptations in Female Mice.

Christian J Elliehausen, Szczepan S Olszewski, Dennis M Minton, Carolyn G Shult, Aditya R Ailiani, Michaela E Trautman, Reji Babygirija, Dudley W Lamming, Troy A Hornberger, Adam R Konopka.

  An increasing number of physically active adults are taking the mTOR inhibitor rapamycin off label with the goal of extending healthspan. However, frequent rapamycin dosing disrupts metabolic health during sedentary conditions and abates the anabolic response to exercise. Intermittent once-weekly rapamycin dosing minimizes many negative metabolic side effects of frequent rapamycin in sedentary mice. However, it remains unknown how different rapamycin dosing schedules impact metabolic, physical, and skeletal muscle adaptations to voluntary exercise training. Therefore, we tested the hypothesis that intermittent rapamycin (2 mg/kg; 1×/week) would avoid detrimental effects on adaptations to 8 weeks of progressive weighted wheel running (PoWeR) in adult female mice (5-month-old) by evading the sustained inhibitory effects on mTOR signaling by more frequent dosing schedules (2 mg/kg; 3×/week). PoWeR improved maximal exercise capacity, absolute grip strength, and myofiber hypertrophy with no differences between vehicle or rapamycin-treated mice despite greater voluntary running volume with intermittent rapamycin treatment. Conversely, frequent and intermittent rapamycin-treated mice had impaired glucose tolerance and insulin sensitivity compared to vehicle-treated mice after PoWeR; however, intermittent rapamycin reduced the impact on glucose intolerance versus frequent rapamycin. Collectively, these data in adult female mice suggest that (1) rapamycin is largely compatible with the physical and skeletal muscle benefits of PoWeR and (2) the detrimental effects of rapamycin on glucose metabolism in the context of voluntary exercise may be reduced by intermittent dosing.

Keywords:   mTOR ; aging; exercise; glucose tolerance; hypertrophy; muscle

DOI:  https://doi.org/10.1111/acel.70183
bioRxiv. 2025 May 07. pii: 2024.11.21.624690. [Epub ahead of print]

Impact of Acute Endurance Exercise on Alternative Splicing in Skeletal Muscle.

Alexander Ahn, Jeongjin J Kim, Aaron L Slusher, Jeffrey Y Ying, Eric Y Zhang, Andrew T Ludlow.

   Purpose: Alternative splicing (AS) is a highly conserved post-transcriptional mechanism, generating mRNA variants to diversify the proteome. Acute endurance exercise appears to transiently perturb AS in skeletal muscle, but transcriptome-wide responses are not well-defined. We aimed to better understand differential AS (DAS) and differential isoform expression (DIE) in skeletal muscle by comparing short-read (SRS) and long-read RNA sequencing (LRS) data.
Methods: Publicly accessible SRS of clinical exercise studies were extracted from the Gene Expression Omnibus. Oxford Nanopore LRS was performed on mouse gastrocnemius before and following treadmill exercise (30m running, n=5 mice/group, 20 total, 10 weeks old). Differential gene expression (DGE) and DIE were analyzed and validated using RT-PCR and immunoblots.
Results: Both SRS and LRS illustrated significant DGE in skeletal muscle post-exercise, including 89 RNA-binding proteins (RBPs). rMATS analysis of SRS revealed that exon-skipping and intron-retaining events were the most common. Swan analysis of LRS revealed several common genes across post-exercise cohorts with significant DAS but no DGE: 13 exercise-associated genes, including mSirt2 (24.5% shift at 24hr post-exercise [24pe], p=0.005); 61 RBPs, including mHnrnpa3 (28.5% at 24pe, p=0.02), mHnrnpa1 (30.6% at 24pe, p=0.004), and mTia1 (53.6% at 24pe, p=0.004).
Conclusions: We illustrated that acute endurance exercise can elicit changes in AS-related responses and RBP expression in skeletal muscle, especially at 24pe. SRS is a powerful tool for analyzing DGE but lacks isoform detection, posing a major gap in knowledge of "hidden" genes with no transcriptional but significant DIE and protein expression changes. Additionally, LRS can uncover previously unknown transcript diversity and mechanisms influencing endurance exercise adaptations and responses.

Keywords:  Endurance exercise; RNA-binding proteins; alternative RNA splicing; skeletal muscle; splicing factors

DOI:  https://doi.org/10.1101/2024.11.21.624690
Korean J Physiol Pharmacol. 2025 Jul 24.

Circular RNA circAtxn10 regulates skeletal muscle cell differentiation by targeting miR-143-3p and Chrna1.

Nakwon Choe, Anna Jeong, Hosouk Joung, Dongtak Jeong, Young-Kook Kim, Hyun Kook, Duk-Hwa Kwon.

  Skeletal muscle differentiation is a complex process regulated by a network of genes and transcription factors. Recent studies have revealed the roles of circular RNAs (circRNAs) and microRNAs (miRNAs) in modulating gene expression during myogenesis. In this study, we focused on the functional interplay between circAtxn10, miR-143-3p, and the nicotinic acetylcholine receptor subunit alpha 1 (Chrna1) in skeletal muscle differentiation. Our results demonstrate that circAtxn10 expression increases during myogenic differentiation and acts as a sponge for miR-143-3p through direct binding. We identified Chrna1 as a direct target of miR-143-3p through three binding sites in its 3'-UTR and showed that both miR-143-3p mimic and Chrna1 knockdown significantly impair myogenesis. Notably, Chrna1 overexpression dramatically enhanced myogenic marker expression and myotube formation. Our findings establish a regulatory axis involving circAtxn10, miR-143-3p, and Chrna1 that plays a critical role in modulating skeletal muscle differentiation, providing new insights into the complex molecular mechanisms regulating myogenesis.

Keywords:  Chrna1; Myogenesis; Skeletal muscle; circRNA; miR-143-3p

DOI:  https://doi.org/10.4196/kjpp.25.046
Am J Physiol Cell Physiol. 2025 Jul 24.

Making Sense of MYC in Skeletal Muscle: Location, Duration, and Magnitude.

Ronald G Jones Iii, Sebastian Edman, Nathan Serrano, Yuan Wen, John J McCarthy, Christopher S Fry, Ferdinand von Walden, Kevin A Murach.



Keywords:  Muscle Fiber; Muscle Hypertrophy; Oncogene; RNA-sequencing; c-MYC

DOI:  https://doi.org/10.1152/ajpcell.00528.2025
Commun Biol. 2025 Jul 19. 8(1): 1074

Tissue-engineered neuromuscular organoids.

Beatrice Auletta, Pietro Chiolerio, Giada Cecconi, Lucia Rossi, Luigi Sartore, Francesca Cecchinato, Gilda Barbato, Agnese Lauroja, Edoardo Maghin, Maria Easler, Paolo Raffa, Silvia Angiolillo, Wei Qin, Roberta Frison, Sonia Calabrò, Chiara Villa, Onelia Gagliano, Cecilia Laterza, Davide Cacchiarelli, Matilde Cescon, Monica Giomo, Yvan Torrente, Camilla Luni, Martina Piccoli, Nicola Elvassore, Anna Urciuolo.

Skeletal muscle development, homeostasis, and function rely on complex interactions among multiple cell types and the extracellular matrix (ECM). Developing in vitro models that recapitulate both intrinsic cellular and extrinsic ECM elements of innervated skeletal muscle is crucial for advancing basic biology and disease modeling studies. Here, we combine tissue engineering approaches with human induced pluripotent stem cell (hiPSC) technology to create tissue-engineered neuromuscular organoids (t-NMOs). Using decellularized muscles as scaffolds, hiPSCs differentiate to form organoids that establish a continuum with the provided biomaterial. After 30 days, t-NMOs exhibit compartmentalized neural and muscular components that establish functional interactions, allowing muscle contraction. We demonstrate the model's potential by creating Duchenne Muscular Dystrophy patient-specific t-NMOs, that recapitulate the reduced skeletal muscle contraction and altered calcium dynamics typical of the disease. Altogether, our study presents a tissue-engineered organoid that model the human neuromuscular system (dys)function, highlighting the potential of applying the ECM in organoid engineering.

DOI: https://doi.org/10.1038/s42003-025-08484-z
J Funct Morphol Kinesiol. 2025 Jul 19. pii: 281. [Epub ahead of print]10(3):

Transcriptional Signatures of Aerobic Exercise-Induced Muscle Adaptations in Humans.

Pranav Iyer, Diana M Asante, Sagar Vyavahare, Lee Tae Jin, Pankaj Ahluwalia, Ravindra Kolhe, Hari Kashyap, Carlos Isales, Sadanand Fulzele.

  Background: Aerobic exercise induces a range of complex molecular adaptations in skeletal muscle. However, a complete understanding of the specific transcriptional changes following exercise warrants further research. Methods: This study aimed to identify gene expression patterns following acute aerobic exercise by analyzing Gene Expression Omnibus (GEO) datasets. We performed a comparative analysis of transcriptional profiles of related genes in two independent studies, focusing on both established and novel genes involved in muscle physiology. Results: Our analysis revealed ten consistently upregulated and eight downregulated genes across both datasets. The upregulated genes were predominantly associated with mitochondrial function and cellular respiration, including MDH1, ATP5MC1, ATP5IB, and ATP5F1A. Conversely, downregulated genes such as YTHDC1, CDK5RAP2, and PALS2 were implicated in vascular structure and cellular organization. Importantly, our findings also revealed novel exercise-responsive genes not previously characterized in this context. Among these, MRPL41 and VEGF were significantly upregulated and are associated with p53-mediated apoptotic signaling and fatty acid metabolism, respectively. Novel downregulated genes included LIMCH1, CMYA5, and FOXJ3, which are putatively involved in cytoskeletal dynamics and muscle fiber type specification. Conclusions: These findings enhance our understanding of the transcriptional landscape of skeletal muscle following acute aerobic exercise and identify novel molecular targets for further investigation in the fields of exercise physiology and metabolic health.

Keywords:  exercise; muscle; transcriptional

DOI:  https://doi.org/10.3390/jfmk10030281
Int J Biol Macromol. 2025 Jul 17. pii: S0141-8130(25)06680-2. [Epub ahead of print]320(Pt 4): 146123

The m6A reader IGF2BP3 facilitates myogenesis by activating the CAMK2B-MEF2C axis.

Zhipeng Liu, Kaiping Deng, Yalong Su, Wurilege Wei, Zhen Zhang, Qingwei Lu, Yang Gao, Ziyu Wang, Hualin Zhao, Yixuan Fan, Guomin Zhang, Yanli Zhang, Feng Wang.

  Skeletal muscle development directly impacts meat quality and productivity in livestock. Although N6-methyladenosine (m6A) RNA methylation has been recognized as a crucial epigenetic mechanism governing myogenesis, the specific functions of Insulin-like Growth Factor 2 mRNA-binding Protein 3 (IGF2BP3), a key m6A reader protein, in goat muscle development remain elusive. This study was designed to dissect the role of IGF2BP3 and its m6A-mediated regulatory mechanisms during goat skeletal muscle development. Our results showed that IGF2BP3 expression was lower in the longissimus muscles of kids and adults than in those of fetuses but increased during in vitro myogenic differentiation. Functional loss-of-function experiments demonstrated that IGF2BP3 depletion led to profound impairments in myoblast proliferation and differentiation. Through a combination of RNA-seq, RIP-qPCR, and mRNA stability assays, we established that IGF2BP3 binds to m6A-modified CAMK2B and MEF2C transcripts. This interaction stabilizes these mRNAs, thereby enhancing gene expression and activating the CAMK2B-MEF2C axis - a newly identified regulatory axis essential for myogenic progression. Our findings not only unveil IGF2BP3 as a pivotal regulator in goat myogenesis but also delineate an m6A-dependent molecular pathway with distinct regulatory features compared to existing models in other species. This novel understanding of epigenetic control in muscle development offers actionable targets for precision breeding strategies, with potential to revolutionize goat meat production by optimizing muscle growth and quality traits.

Keywords:  CAMK2B-MEF2C axis; IGF2BP3; Myogenesis; Post-transcriptional regulation; m6A

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.146123
Front Endocrinol (Lausanne). 2025 ;16 1608612

Unraveling the role of STAT3 in Cancer Cachexia: pathogenic mechanisms and therapeutic opportunities.

Xinyi Lv, Shengguang Ding.

  Cancer cachexia is a complex, multifactorial syndrome characterized by severe weight loss, muscle wasting, and systemic inflammation, significantly contributing to cancer-related morbidity and mortality. Signal transducer and activator of transcription 3 (STAT3) has emerged as a central mediator in the pathogenesis of this multifactorial condition. STAT3 regulates a broad range of cellular processes including inflammation, proteolysis, and mitochondrial dysfunction across multiple tissues, particularly skeletal muscle and adipose tissue. Persistent activation of STAT3 in response to tumor-derived and host-derived cytokines drives catabolic signaling cascades, disrupts anabolic pathways, and impairs energy homeostasis. Recent studies have illuminated the cross-talk between STAT3 and other signaling pathways that exacerbate cachexia-related metabolic imbalances. These findings position STAT3 not only as a critical mediator of cachexia progression but also as a promising therapeutic target. Pharmacological inhibition of STAT3 signaling has demonstrated efficacy in preclinical models, offering potential avenues for clinical intervention. This review provides a comprehensive overview of the molecular mechanisms by which STAT3 contributes to cancer cachexia and discusses emerging therapeutic strategies aimed at modulating STAT3 activity to mitigate the progression of this debilitating syndrome.

Keywords:  STAT3; cancer cachexia; muscle wasting; pathogenic mechanisms; systemic inflammation; therapeutic strategies

DOI:  https://doi.org/10.3389/fendo.2025.1608612
Bioeng Transl Med. 2025 Jul;10(4): e70009

In vivo evaluation of decellularized skeletal muscle matrices for skeletal muscle repair: A systematic review.

Ina Hennion, Charlot Philips, Chong Jiang, Nele Van De Winkel, Laurens J Ceulemans, Lieven Thorrez.

  Volumetric muscle loss is the significant loss of skeletal muscle volume beyond the innate regenerative capacity, resulting in functional impairment. The current standard of care combines muscle autografting with physical therapy but is often insufficient to reach full recovery. Decellularized skeletal muscle (DSM) provides an interesting alternative to repair volumetric muscle loss. The native structure and composition of the extracellular matrix in these acellular implants provide a blueprint for muscle regeneration. Moreover, DSM can be combined with cells to facilitate the regeneration of the skeletal muscle defect. This systematic review provides a complete and thorough overview of the state-of-the-art applications and efficacy of DSM matrices in skeletal muscle repair in vivo, selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Technical information on the different methods to create DSM implants and the implantation studies is provided. Moreover, details on the evaluation of the structural and functional regeneration of the muscle defect after implantation of the DSM are described. Results reveal a large heterogeneity in the analysis of regeneration upon DSM implantation. This heterogeneity makes it difficult to fully assess the efficiency of DSM to regenerate skeletal muscle, hampering further translation of this technique. Therefore, we suggest a multi-level evaluation method to assess (i) muscle regeneration, (ii) vascularization, (iii) innervation of the regenerated muscle, and (iv) functional regeneration in a quantitative way.

Keywords:  acellular matrix; decellularization; preclinical models; recellularization; skeletal muscle regeneration; tissue engineering; volumetric muscle loss

DOI:  https://doi.org/10.1002/btm2.70009
Front Endocrinol (Lausanne). 2025 ;16 1601474

Physiological processes induced by different types of physical activity that either oppose or enhance postprandial glucose tolerance.

Marc T Hamilton, Deborah G Hamilton, Theodore W Zderic.

  Herein, we describe overlooked/misunderstood physiological processes (beyond contraction-induced skeletal muscle insulin sensitivity that is already well appreciated) that either oppose or enhance glucose tolerance during distinct types of acute physical activity. This includes multiple mechanisms both within and outside of muscle. We describe the processes and physiological principles to help explain why postprandial glucose tolerance is often not improved after acute bouts of exercise, or when interrupting prolonged sitting with either brief physical activity breaks or more prolonged standing. We also describe results from a specialized type of soleus muscle activity that is specifically well-geared to amplify and sustain oxidative muscle metabolism for long periods of time when sitting, with evidence that this has meaningful positive effects on systemic glucose and lipid regulation. Methods capable of elevating oxidative muscle metabolism could be advantageous to complement other lifestyle and pharmacological approaches whose mechanisms of action are limited to non-oxidative metabolic pathways. There is much potential need for inducing more oxidative muscle metabolism, because the entire musculature normally accounts for only about 15% of the oxidative metabolism of glucose when sitting inactive, despite being the body's largest lean tissue mass. A clear understanding of the multiple integrative processes that either tend to attenuate or amplify blood glucose excursions in the postprandial period is significant, given the strong influence of glucose tolerance on healthy aging and prevention of multiple chronic diseases.

Keywords:  exercise; glycogen; impaired glucose tolerance; oral glucose tolerance; physical activity; sedentary; soleus; type 2 diabetes

DOI:  https://doi.org/10.3389/fendo.2025.1601474
Prog Lipid Res. 2025 Jul 16. pii: S0163-7827(25)00024-4. [Epub ahead of print]99 101342

The endocannabinoid system & malignant hyperthermia: From molecular signaling towards clinical implications.

Simon Dalle, Sebastiaan Dalle.

  Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disorder triggered by volatile anaesthetics and depolarizing muscle relaxants. MH is characterized by excessive calcium release from the sarcoplasmic reticulum, often due to ryanodine receptor 1 (RYR1) mutations, leading to hypermetabolism, muscle rigidity and hyperthermia. While the RYR1 antagonist dantrolene remains the primary pharmacological treatment, its side effects necessitate exploration of alternative treatment options. Emerging evidence implicates the endocannabinoid system in muscle calcium homeostasis, suggesting its potential role in MH management. The endocannabinoid system comprises endogenous ligands (e.g. anandamide), cannabinoid receptors (e.g. cannabinoid receptor 1, CB1), and can modulate the calcium dynamics. CB1 activation inhibits PKA-mediated phosphorylation of RYR1 and L-type calcium channels, reducing myoplasmic calcium and muscle contractility, a mechanism that could counteract MH pathophysiology. In addition, antagonism or desensitization of the calcium channel transient receptor potential vanilloid 1 lowers calcium release from the sarcoplasmic reticulum. Preclinical studies demonstrate that CB1 agonism lowers body temperature and attenuates cardiovascular stress, aligning with MH therapeutic goals. This review synthesizes molecular insights linking endocannabinoid signaling to MH, highlighting its unexplored potential as an adjunctive therapy. Future research should validate these mechanisms in MH-specific models, including RYR1-mutant human myotubes, to translate ECS modulation into clinical practice.

Keywords:  Calcium homeostasis; Cannabidiol; Cannabinoid receptor; Dantrolene; Endocannabinoid system; Malignant hyperthermia; Skeletal muscle

DOI:  https://doi.org/10.1016/j.plipres.2025.101342
Acta Neuropathol Commun. 2025 Jul 23. 13(1): 160

Gene therapy ameliorates neuromuscular pathology in CLN3 disease.

Ewa A Ziółkowska, Albina Jablonka-Shariff, Letitia L Williams, Matthew J Jansen, Sophie H Wang, Elizabeth M Eultgen, Matthew D Wood, Daniel A Hunter, Jaiprakash Sharma, Marco Sardiello, Robyn Reese, Alan Pestronk, Mark S Sands, Alison K Snyder-Warwick, Jonathan D Cooper.

  CLN3 disease is a neuronopathic lysosomal storage disorder that severely impacts the central nervous system (CNS) while also inducing notable peripheral neuromuscular symptoms. Although considerable attention has been directed towards the neurodegenerative consequences within the CNS, the involvement of peripheral tissues, including skeletal muscles and their innervation, has been largely neglected. We hypothesized that, CLN3 deficiency could directly influence peripheral nerves and investigated the neuromuscular system in Cln3Δex7/8 mice. Our study found no overt loss of sciatic nerve axons or demyelination in 18-month-old Cln3Δex7/8 mice at disease endstage, but a marked reduction of terminal Schwann cells (tSCs) at lower limb neuromuscular junctions (NMJs), culminating in progressive denervation of these NMJs which appeared abnormal. This led us to investigate skeletal muscle where we found significant myofiber atrophy and decreased and misplaced myofibril nuclei. Similar myopathic alterations were present in a muscle biopsy from an 8-year-old human CLN3 patient shortly after diagnosis. To assess a potential therapeutic intervention, we administered intravenous gene therapy using AAV9.hCLN3 to neonatal Cln3Δex7/8 mice, which at disease endstage, entirely prevented tSC loss and NMJ abnormalities, while also averting skeletal muscle atrophy. These findings underscore the underappreciated, yet substantial effects of CLN3 disease beyond the CNS, highlighting peripheral neuromuscular pathologies as novel features of this disorder. Our findings also indicate that these manifestations could be amenable to treatment via gene therapy, opening new therapeutic strategies in the management of CLN3 disease.

Keywords:  AAV9 gene therapy; CLN3 disease; Muscle atrophy; Neuromuscular junction; Peripheral nervous system; Terminal Schwann cells

DOI:  https://doi.org/10.1186/s40478-025-02059-z
Biol Pharm Bull. 2025 ;48(7): 1079-1088

Calsequestrin-1 Deficiency Induced Malignant Hyperthermia-Like Skeletal Injury through Mitochondrial Disorder.

Xintong Guo, Xin Geng, Hanying Zhang, Ronghua Liu, Qiang Li, Zhiyi Li, Yimeng Zhang, Lingxi Zhang, Zhiping Fu, Luqi Wang, Hongjie You, Jingyi Xue, Dali Luo.

  Calsequestrin-1 (CASQ1) is a candidate gene defect for malignant hyperthermia (MH) with significant skeletal muscle symptoms and injury, in which mitochondrial dysfunction may play an important role. However, the mechanisms underlying the mitochondrial changes are unknown. In this study we aimed to investigate the possible mechanisms for mitochondrial disorder using calseguestrin-1 knockout (Casq1-KO) mice. Casq1-KO mouse skeletal muscle injury was detected by the measurement of grip strength, and hematoxylin-eosin (H&E) and Gomori immune-staining. Mitochondrial function was evaluated by assessments of membrane potential (MMP), ATP production, and mitochondrial Ca2+ level. Western blot and malondialdehyde (MDA) assays were used to evaluate mitochondrial oxidative stress. AAV9-carrying CMV-Casq1 gene transfection was applied to confirm the effect of Casq1 deficiency on the skeletal muscle. The results showed that Casq1-KO mice exhibited obvious skeletal muscle dysfunction, structural change, and promotions of reactive oxygen species (ROS) production and its signal pathway activation. Significant decreases in ATP production and MMP, and an increase in mitochondrial Ca2+ level were observed in Casq1-KO skeletal mitochondria compared with those of WT. Interestingly, the expression of mitochondrial Ca2+ channel (MICU1), an important mitochondrial Ca2+ regulatory protein, was remarkably reduced in Casq1-KO skeletal mitochondria. Transduction of AAV9-CMV-Casq1 into Casq1-KO skeletal muscle recovered the Casq1 and MICU1 expression, mitochondrial Ca2+ level, MMP, and ATP production, with significant mitigation of skeletal oxidative stress and injuries. In conclusion, Casq1 deficiency or dysfunction could induce skeletal muscle injuries directly. Depressed MICU1 expression with an increased mitochondrial Ca2+ and ROS production may contribute significantly to the skeletal myopathy in malignant hyperthermia-like skeletal syndrome.

Keywords:  calsequestrin-1; malignant hyperthermia; mitochondrial Ca2+; mitochondrial dysfunction

DOI:  https://doi.org/10.1248/bpb.b24-00829
Am J Pathol. 2025 Jul 17. pii: S0002-9440(25)00243-3. [Epub ahead of print]

Alcohol mediated skeletal muscle adaptations and their impact on comorbidities.

Keishla M Rodríguez-Graciani, Paticia E Molina, Liz Simon.

  At-risk alcohol use has significant adverse effects on multiple tissue and organ systems, including the skeletal muscle. The pathophysiological mechanisms underlying alcohol-induced dysfunctional skeletal muscle mass are multifactorial, involving decreased protein synthesis, increased protein degradation, impaired glucose homeostasis, bioenergetic dysregulation, aberrant extracellular matrix remodeling, impaired satellite cell function, circadian rhythm disruption, and epigenomic adaptations. This review provides a brief overview of these major alcohol-induced mechanisms of skeletal muscle dysfunction. Additionally, the review examines the current literature on alcohol-mediated skeletal muscle maladaptations in the context of comorbidities such as aging, alcohol-related liver disease, systemic and diet-induced metabolic dysregulation, cancer cachexia, and musculoskeletal pain. While alcohol-induced skeletal muscle alterations may function as both the cause and consequence of these comorbid conditions, critical research gaps remain, particularly in the need for systematic clinical studies complemented by preclinical mechanistic research. Notably, 40-60% of people with at-risk alcohol use exhibit skeletal muscle maladaptations, yet data on associated healthcare or productivity loss costs are lacking. A comprehensive understanding of alcohol-induced skeletal muscle dysfunction is warranted for developing targeted interventions to reduce healthcare costs and improve quality of life in this population.

Keywords:  alcohol; comorbidities; pathophysiological mechanism; skeletal muscle

DOI:  https://doi.org/10.1016/j.ajpath.2025.05.025
Eur J Transl Myol. 2025 Jul 23.

Impact of myokines on chronic liver diseases: exploring the effects of metabolic dysfunction-associated steatotic liver disease (MASLD) on skeletal muscle. A narrative review.

Francisco Aguirre, Mayalen Valero-Breton, Daniel Cabrera, Luis Peñailillo, María Carolina Otero, Claudia Fredes, Claudio Cabello-Verrugio.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a condition characterized by altered liver function due to fatty accumulation, which can lead to liver inflammation and, in advanced stages, liver carcinoma. MASLD is closely linked to several metabolic alterations, such as obesity and insulin resistance, which directly affect skeletal muscles and contribute to the development of sarcopenia. Sarcopenia is the loss of muscle mass and strength, leading to decreased physical performance in severe stages. Skeletal muscles secrete molecules known as myokines under various conditions, such as exercise or diseases like MASLD. These myokines modulate communication between the skeletal muscle and other tissues. These myokines regulate muscle mass and, in pathological conditions, contribute to the development of sarcopenia. Emerging evidence highlights the crucial role of myokines in regulating skeletal muscle metabolism and function in MASLD. Myokines influence muscle metabolism, inflammation, and insulin sensitivity, offering potential therapeutic targets for managing muscle atrophy and sarcopenia in the context of MASLD. Understanding the interaction between myokines and skeletal muscle may lead to novel interventions to mitigate MASLD progression and sarcopenia. This review examines the mechanisms by which myokines regulate skeletal muscle metabolism and function in the context of MASLD.

DOI: https://doi.org/10.4081/ejtm.2025.13365
Clin Transl Med. 2025 Jul;15(7): e70404

PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease.

Swagat Pradhan, Takayuki Mito, Nahid A Khan, Sofiia Olander, Aleksandra Zhaivoron, Thomas G McWilliams, Anu Suomalainen.

   BACKGROUND: Mitochondria elicit various metabolic stress responses, the roles of which in diseases are poorly understood. Here, we explore how different muscles of one individual-extraocular muscles (EOMs) and quadriceps femoris (QFs) muscles-respond to mitochondrial disease. The aim is to explain why EOMs atrophy early in the disease, unlike other muscles.
METHODS: We used a mouse model for mitochondrial myopathy ("deletor"), which manifests progressive respiratory chain deficiency and human disease hallmarks in itsmuscles. Analyses included histology, ultrastructure, bulk and single-nuclear RNA-sequencing, metabolomics, and mitochondrial turnover assessed through in vivo mitophagy using transgenic mito-QC marker mice crossed to deletors.
RESULTS: In mitochondrial muscle disease, large QFs upregulate glucose uptake that drives anabolic glycolytic one-carbon metabolism and mitochondrial integrated stress response. EOMs, however, react in an opposite manner, inhibiting glucose and pyruvate oxidation by activating PDK4, a pyruvate dehydrogenase kinase and inhibitor. Instead, EOMs upregulate acetyl-CoA synthesis and fatty-acid oxidation pathways, and accumulate lipids. In QFs, Pdk4 transcription is not induced.- Amino acid levels are increased in QFs but are low in EOMs suggesting their catabolic use for energy metabolism. Mitophagy is stalled in both muscle types, in the most affected fibers.
CONCLUSIONS: Our evidence indicates that different muscles respond differently to mitochondrial disease even in one individual. While large muscles switch to anabolic mode and glycolysis, EOMs actively inhibit glucose usage. They upregulate lipid oxidation pathway, a non-optimal fuel choice in mitochondrial myopathy, leading to lipid accumulation and possibly increased reliance on amino acid oxidation. We propose that these consequences of non-optimal nutrient responses lead to EOMatrophy and progressive external ophthalmoplegia in patients. Our evidence highlights the importance of PDK4 and aberrant nutrient signaling underlying muscle atrophies.

Keywords:  integrated stress response; mitochondrial disease; mitochondrial myopathy; nutrient signaling; progressive external ophthalmoplegia; pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.1002/ctm2.70404
STAR Protoc. 2025 Jul 21. pii: S2666-1667(25)00368-5. [Epub ahead of print]6(3): 103962

Protocol for investigating chromatin architecture in adult skeletal muscle stem cells using high-throughput chromosome conformation capture.

Jinjin Kang, Yaxin Zeng, Nianle Li, Liangqiang He, Huating Wang, Kun Sun, Yu Zhao.

  3D genome architecture is pivotal for gene transcription and cellular lineage development. However, it remains challenging to generate high-quality Hi-C (high-throughput chromosome conformation capture) libraries from rare cell populations. Here, we present a protocol for investigating chromatin architecture in adult skeletal muscle stem cells, also known as satellite cells (MuSCs), using Hi-C. We detail the procedures for isolating MuSCs, provide an in-depth guide for preparing Hi-C libraries, and introduce the use of the Microcket package for processing Hi-C data. For complete details on the use and execution of this protocol, please refer to Zhao et al.1 and Zhao et al.2.

Keywords:  Genomics; Sequence analysis; Stem cells

DOI:  https://doi.org/10.1016/j.xpro.2025.103962
Curr Issues Mol Biol. 2025 May 19. pii: 371. [Epub ahead of print]47(5):

Effects of Aerobic Exercise on Irisin and Skeletal Muscle Autophagy in ApoE-/- Mice.

Wenxin Wang, Fengting Zheng, Jiawei Zhou, Yangfan Cao, Liang Zhang, Yao Lu, Qingbo Li, Ting Li, Mallikarjuna Korivi, Lifeng Wang, Wei Li.

  As a chronic inflammatory disease, atherosclerosis can affect the occurrence of skeletal muscle autophagy through a variety of mechanisms. Previous studies have demonstrated that exercise enhances autophagic activity through irisin-mediated pathways. Building upon this evidence, this study investigated the effects of a 12-week aerobic exercise training on irisin levels and skeletal muscle autophagy-related proteins in atherosclerotic mice. Male C57BL/6J and ApoE-/- mice were randomly assigned to four groups: Control Group (C), Aerobic Exercise Group (CE), ApoE-/- Control Group (AC), and ApoE-/- Aerobic Exercise Group (AE). Serum and muscle irisin levels were measured by ELISA; the expression levels of FNDC5, AMPK/mTOR pathway proteins and autophagy markers were detected by immunoblots, and muscle morphology was examined using H&E staining. Compared with the C group, the serum levels of TAG, TC, and LDL-C were higher than the AC group. Aerobic exercise increased irisin levels in skeletal muscle, upregulated the expression of LKB1 and p-AMPK, and presented an elevated LC3-II/I ratio, accompanied by reduced mTORC1 expression in CE mice. Aerobic exercise increased FNDC5 expression and irisin levels in serum and skeletal muscle, but also upregulated mTORC1 expression and reduced the LC3-II/I ratio in the AE group. Aerobic exercise enhances irisin synthesis and improves dyslipidemia in ApoE-/- mice. However, the increased expression of the mTORC1 protein contributed to decreasing the expression of autophagy-related proteins following exercise.

Keywords:  aerobic training; atherosclerosis; autophagy; irisin; skeletal muscle

DOI:  https://doi.org/10.3390/cimb47050371
Eur J Intern Med. 2025 Jul 23. pii: S0953-6205(25)00298-5. [Epub ahead of print]

Effect of sodium-glucose cotransporter-2 inhibitors on skeletal muscle.

Claudia Stöllberger, Josef Finsterer, Birke Schneider.

  Empagliflozin and dapagliflozin, frequently prescribed Sodium-Glucose- Cotransporter2-inhibitors (SGLT2i), are now also recommended for nondiabetic patients with heart failure (HF). Since concerns exist about myopathy and sarcopenia as adverse effects of SGLT2i, the review summarizes effects of dapagliflozin and empagliflozin on skeletal muscle. PubMed was searched for "SGLT2" OR "SGLT2 inhibitors" OR "SGLT2i" OR "dapagliflozin" OR "empagliflozin" AND "myopathy" OR "sarcopenia" OR "skeletal muscle" OR "muscle loss" OR "muscle weakness" OR "muscle wasting" OR "myotoxicity" OR "muscle atrophy" OR "rhabdomyolysis". Excluded were reviews, editorials, study protocols, letters to the editor, in vitro and in vivo studies. Myopathy/rhabdomyolysis were reported in 5 patients, 3 with concomitant statins, whereas 3 clinical/pharmacovigilance studies found no increased myopathy/rhabdomyolysis-risk with a SGLT2i-statin-combination. SGLT2i-associated sarcopenia was studied in small cohorts (<100 patients in 65 % of the studies), with diabetes-mellitus (68 %) and Japanese (53 %). Observation time was >6 months in only 32 % of the studies, HF-patients were included in 26 %. Controversial data are reported for muscle-mass, which decreased in 15 and remained unchanged in 6 studies. Physical-performance-tests remained unchanged under SGLT2i. Muscle-biopsies found SGLT2i-assosciated metabolic changes and myofiber-atrophy, but no correlation with functional tests were reported. Exercise or dietary measures did not influence SGLT2i-associated loss of muscle-mass. Two pharmacovigilance studies identified SGLT2i as risk factors for sarcopenia. Data on SGLT2i-associated effects on skeletal muscle are limited and controversial. There is an urgent need for research, especially in nondiabetic, non-Japanese and HF-patients. Since sarcopenia develops over time, observation periods of >12 months are necessary.

Keywords:  Dapagliflozin; Empagliflozin; Myopathy; Sarcopenia

DOI:  https://doi.org/10.1016/j.ejim.2025.07.016
Compr Physiol. 2025 Aug;15(4): e70030

Mechanisms of Exercise in Improving Sarcopenia.

Mengzhu Su, Yingchun Shao, Qun Fang, Yansong Li, Fanghui Qiu, Tongtong Che, Shuangshuang Zhang.

  The global aging population is driving age-related diseases to become a significant public health challenge. Sarcopenia, an age-related condition marked by muscle mass loss, reduced muscle strength, and/or diminished physical function, contributes to a higher incidence of falls, fractures, hospitalizations, and mortality among affected individuals. Exercise is widely recognized as an affordable and sustainable approach to preventing and managing sarcopenia. This review explores the pathogenesis of sarcopenia, examines how various exercise modalities influence its underlying mechanisms, and elucidates the molecular pathways through which exercise mitigates the condition. By providing a thorough overview, this review aims to identify potential therapeutic targets for sarcopenia, ultimately supporting efforts to reduce the burden on global healthcare systems and address the challenges of an aging population.

Keywords:  autophagy; exercise; mitochondrial function; sarcopenia; satellite cells

DOI:  https://doi.org/10.1002/cph4.70030
J Neuropathol Exp Neurol. 2025 Jul 23. pii: nlaf088. [Epub ahead of print]

Intracellular amyloidosis in peripheral nerve and skeletal muscle.

Grace K Grafham, Gloria Mak, Sandra Grant, Alison Murphy, Steven K Baker, Mark Tarnopolsky, Jian-Qiang Lu.

  Amyloidosis is an etiologically heterogeneous group of disorders pathologically characterized by the extracellular deposition of amyloid fibrils, leading to tissue damage. It commonly affects the peripheral nervous system and occasionally involves skeletal muscle. The pathogenic mechanisms driving cellular injury in amyloidosis remain elusive. In this study, we examined 3 sural nerve and 5 skeletal muscle biopsies from patients with amyloidosis to localize the deposition of amyloid fibrils. Histologically, the nerve biopsies showed axonal degeneration and Schwann cell (SC) changes; muscle biopsies demonstrated variable myopathic and neurogenic features with multifocal amyloid deposition, including within intramuscular nerves. Electron microscopy identified both intracellular and extracellular amyloid deposition in all 8 biopsies. The ultrastructural localization of amyloid fibrils included the nerve and muscle extracellular matrix, as well as the SC processes, peri-/sub-sarcolemmal region of non-necrotic myofibers, and endoneurial and endomysial/perimysial blood vessel cells. Notably, SC processes, particularly bands of Büngner, formed amyloid-related complex inclusions in all 3 nerve cases. These findings suggest that intracellular amyloid deposition is common in peripheral nerve and skeletal muscle and may play a significant role in cellular injury and degeneration, and ultimately the progression of neuropathy and myopathy.

Keywords:  amyloid fibril; amyloidosis; electron microscopy; intracellular pathology; myopathy; neuropathy; tissue biopsy

DOI:  https://doi.org/10.1093/jnen/nlaf088
Front Physiol. 2025 ;16 1616693

Targeting ERRs to counteract age-related muscle atrophy associated with physical inactivity: a pilot study.

Roberto Bonanni, Angela Falvino, Antonio Matticari, Anna Maria Rinaldi, Giovanna D'Arcangelo, Pierangelo Cifelli, Riccardo Iundusi, Elena Gasbarra, Virginia Tancredi, Ida Cariati, Umberto Tarantino.

   Introduction: Estrogen-related receptors has been suggested as a potential therapeutic target to counteract muscle decline associated with aging or inactivity, being known to regulate mitochondrial function and cellular respiration by up-regulating key factors in muscle responses to exercise. This study aimed to evaluate the targeting of ERRs in myoblasts isolated from the skeletal muscle of inactive women by assessing the metabolic and expression changes associated with its activation.
Methods: Twenty women undergoing hip arthroplasty for coxarthrosis were enrolled and divided into an active group (n = 10) and an inactive group (n = 10) based on self-reported physical activity. During surgery, muscle biopsies were taken for histological and western blotting analysis, measuring the expression levels of NADPH oxidase 4 (NOX4), sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), estrogen related receptor alpha (ERRα), and fibronectin type III domain-containing protein 5 (FNDC5). Primary cultures of myoblasts were set up from the muscle tissue of inactive women and treated with the ERRs agonist, SLU-PP-332, for subsequent qualitative and quantitative investigations. In addition, myoblasts were differentiated into myotubes for 15 days, and the success of differentiation was evaluated by immunofluorescence analysis.
Results: Clinical and instrumental evaluation showed less functional limitation, higher handgrip strength values, and significantly reduced visual analogue scale scores in active subjects, in association with a significant increase in muscle fiber diameter. In addition, significantly higher expression of NOX4, concomitant with reduced levels of SIRT1, PGC-1α, ERRα, and FNDC5, was detected in the muscle tissue of inactive women. Interestingly, SLU-PP-332 treatment promoted down-regulation of NOX4 and upregulation of SIRT1, PGC-1α, ERRα, FNDC5, Akt, and B-cell lymphoma 2 (Bcl-2) in myoblasts, reducing cytotoxicity, oxidative stress, and senescence, as well as increasing levels of reduced glutathione. Furthermore, SLU-PP-332 treatment promoted abundant myotube formation, positively influencing cell differentiation.
Discussion: Targeting ERRs could represent a promising therapeutic strategy to counteract muscle atrophy in elderly and sedentary subjects. However, further studies are needed to clarify the molecular mechanisms involved and explore the impact of ERRs activation on muscle metabolism.

Keywords:  ERRs; aging; biomarkers; physical inactivity; physiology; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2025.1616693
Int J Physiol Pathophysiol Pharmacol. 2025 ;17(3): 80-93

State-of-the-art insights into myokines as biomarkers of sarcopenia: a literature review.

Omar R Moussaoui, Ioannis Deligiannis, Petar-Preslav Petrov, Tsvetelina Velikova, Yavor Assyov.

  Sarcopenia is an age-associated progressive deterioration of skeletal muscle, not only affecting the muscle function of elderly individuals but also contributing to various health issues and increased mortality. Current diagnostic tools are faced with limitations, hindering their widespread clinical application. This review examines the potential of myokines, peptides released from contracting muscles, as innovative biomarkers for sarcopenia. We explore the wide range of auto-, para-, and endocrine functions of myokines and the pathways of their physiological action, as well as address ongoing research results on the role of myokines as biomarkers for the timely diagnosis of sarcopenic individuals. Of all myokines, the ones that show the highest potential include irisin, myostatin, follistatin and brain-derived neurotrophic factor (BDNF). Their physiological action is exerted through complex pathways involving multiple molecules. Most studies show that these molecules can be used as biomarkers for the timely diagnosis of sarcopenia, whether by using each one individually or as a panel of biomarkers. However, several studies showed no correlation between the plasma levels of these peptides and a sarcopenia diagnosis. Finally, a number of studies also exhibited gender-affected relationships. While the quality of studies is promising, research on the use of myokines as biomarkers of sarcopenia is needed to more accurately determine the cut-off plasma values of such markers. By overcoming the shortcomings of existing methodologies, utilizing myokines in daily clinical practice could offer a promising path toward more effective prevention, diagnosis, and treatment strategies, ultimately improving outcomes for the aging population.

Keywords:  Sarcopenia; biomarker; brain-derived neurotrophic factor; follistatin; irisin; myokine(s); myostatin

DOI:  https://doi.org/10.62347/RNEQ8696
Muscle Nerve. 2025 Jul 18.

Advances in MicroRNAs in Pathophysiology of Duchenne Muscular Dystrophy.

Jose Emilio Galeazzi Aguilar, Tomas Almeida-Becerril, Maricela Rodríguez-Cruz.

  Duchenne muscular dystrophy (DMD) is a severe, progressive muscle disorder caused by pathogenic variants in the DMD gene, which encodes dystrophin, a protein essential for maintaining muscle integrity. Reduced or absent dystrophin expression results in sarcolemmal instability, chronic inflammation, oxidative stress, impaired muscle regeneration, and fibrosis. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally and significantly influence multiple pathological processes in DMD. Specific miRNAs, including miR-146a, miR-155, miR-378, and miR-711, modulate inflammation primarily through the NF-κB signaling pathway. Others, such as miR-21, miR-31, miR-128, miR-144, and miR-379, regulate oxidative stress responses via the NRF2 antioxidant pathway. Muscle-specific miRNAs (myomiRs), notably miR-1, miR-133a/b, miR-206, miR-486, and miR-499, are critical for muscle regeneration, and their dysregulation impairs satellite cell function and muscle repair. Additionally, miRNAs such as miR-21, miR-29a/c, and miR-199a-5p play significant roles in fibrosis development. The dysregulation of these miRNAs contributes to the complex pathophysiology of DMD, underscoring their potential as biomarkers for disease progression and therapeutic response. Understanding the specific roles of these miRNAs provides valuable insights into the molecular mechanisms underlying DMD and may facilitate the identification of novel therapeutic targets.

Keywords:  Duchenne muscular dystrophy; MiRNAs; inflammation; muscle regeneration; oxidative stress

DOI:  https://doi.org/10.1002/mus.28482
Appl Physiol Nutr Metab. 2025 Jul 24.

Mechanisms of Muscle Atrophy in Type 2 Diabetes Mellitus: Factors Dysregulating Muscle Protein Synthesis and Breakdown.

Moses Jeong, Taylor McColl, David Clarke.

Type 2 diabetes mellitus (T2DM) is rising in prevalence and incidence, which is leading to increased burden on healthcare systems. A less recognized consequence of T2DM is the accelerated loss of skeletal muscle, which can reduce quality of life and further exacerbate T2DM progression. Insulin resistance disrupts skeletal muscle maintenance by impairing insulin- and leucine-mediated signalling - processes challenging to study due to the number and complexity of dysregulated components. Several key areas in this field remain underexplored, such as the causal relationship between T2DM and muscle atrophy, the impact of insulin resistance on muscle protein balance, and the mechanisms driving muscle atrophy in humans with T2DM. Advancing understanding in these areas requires the integration of evidence from experimental, prospective, and computational studies to more precisely characterize the mechanisms and progression of T2DM-related muscle atrophy and to inform targeted interventions to mitigate muscle loss.

DOI: https://doi.org/10.1139/apnm-2025-0017
Cell Genom. 2025 Jul 16. pii: S2666-979X(25)00207-1. [Epub ahead of print] 100951

Impact of polymorphisms on gene expression and splicing in response to exercise and diet-induced weight loss in human skeletal muscle tissues.

Wenjing Wang, Wei Lin Liew, Shiqi Huang, Edmund Chan, Amelia Li Min Tan, Chi Tian, Yihan Tong, Yuntian Zhang, Fei Liu, Yixian Qin, Sean Jun Leong Ou, Suresh Anand Sadananthan, Sambasivam Sendhil Velan, Kavita Venkataraman, Sarah R Langley, Petretto Enrico, Shawn Hoon, Kwang Wei Tham, Yap Seng Chong, Yung Seng Lee, Melvin Khee-Shing Leow, Xueling Sim, Chin Meng Khoo, E Shyong Tai, Eric Yin Hao Khoo, Mei Hui Liu, Boxiang Liu.

  Weight loss through exercise and diet reduces the risk of type 2 diabetes, but the genetic regulation of gene expression and splicing in response to weight loss remains unclear in humans. We collected clinical data and skeletal muscle biopsies from 54 overweight/obese Asian individuals before and after a 16-week lifestyle intervention, which resulted in an average of ∼10% weight loss, accompanied by an ∼30% increase in insulin-stimulated glucose uptake. Improvements were observed in 118 of 252 clinical traits and six blood lipids. Transcriptomic analysis of paired skeletal muscle biopsies identified 505 differentially expressed genes enriched in mitochondrial function and insulin sensitivity. Thousands of muscle-specific expression/splicing quantitative trait loci (e/sQTLs) were detected pre- and post-intervention, including hundreds of lifestyle-responsive e/sQTLs. Notably, approximately 4.2% of eQTLs and 7.3% of sQTLs showed Asian specificity. Joint analysis with genome-wide association study (GWAS) identified 16 putative metabolic risk genes. Our study reveals gene-by-lifestyle interactions and how lifestyle modulates gene regulation in skeletal muscle.

Keywords:  Asian-specific QTL; gene-by-lifestyle interaction; human intervention study; lifestyle modifications; metabolic disease; skeletal muscle transcriptomics; weight loss

DOI:  https://doi.org/10.1016/j.xgen.2025.100951
J Hum Genet. 2025 Jul 22.

Molecular genetics of J-domain protein-related chaperonopathies in skeletal muscle.

Michio Inoue.

The J-domain proteins (JDPs), or HSP40s, are essential molecular co-chaperones that, in concert with HSP70, play a pivotal role in maintaining protein homeostasis, which is particularly critical in skeletal muscle. In recent years, pathogenic variants in several JDP-encoding genes have been identified as a cause of a growing group of inherited muscle diseases, termed JDP-related myopathies. This review provides a comprehensive overview of the current understanding of the molecular genetics, clinical phenotypes, muscle pathology, and pathomechanisms of myopathies caused by mutations in DNAJB6, DNAJB4, and DNAJB2. These disorders present with a wide spectrum of clinical features, including limb-girdle or distal weakness, and, in some cases, severe early-onset respiratory failure with axial rigidity. Pathologically, they are often characterized by rimmed vacuoles and sarcoplasmic protein inclusions. The underlying molecular mechanisms all involve disruption of the JDP-HSP70 chaperone system, but they are driven by distinct molecular events specific to each gene and mutation type. While loss-of-function is a primary mechanism for recessive forms of DNAJB4 and DNAJB2 myopathy, a toxic gain-of-function mediated by a dysregulated interaction with HSP70 is emerging as a central pathomechanism for dominant myopathies caused by DNAJB6 and DNAJB4 variants. A dominant-negative effect is proposed for dominant DNAJB2 neuromyopathy. This evolving mechanistic understanding is crucial as it informs the development of targeted therapeutic strategies, moving beyond supportive care. Potential future therapies include gene replacement for loss-of-function disorders, and for gain-of-function diseases, approaches including small molecule inhibitors of the JDP-HSP70 interaction or allele- and isoform-specific knockdown.

DOI: https://doi.org/10.1038/s10038-025-01372-8
Dev Cell. 2025 Jul 15. pii: S1534-5807(25)00411-3. [Epub ahead of print]

Microtubules coordinate mitochondria transport with myofibril morphogenesis during muscle development.

Jerome Avellaneda, Duarte Candeias, Ana da Rosa Soares, Edgar R Gomes, Nuno Miguel Luis, Frank Schnorrer.

  Muscle cells contain numerous energy-producing mitochondria and contractile myofibrils, whose myosin motors need ATP to generate force. Thus, myofibrils and mitochondria are in intimate contact in mature muscles. However, how their morphogenesis is coordinated during development remains largely unknown. Here, we used in vivo imaging to investigate myofibril and mitochondria network dynamics in developing Drosophila flight muscles. We found that mitochondria intercalate from the surface of actin bundles to their interior, and concomitantly, actin filaments condense to individual myofibrils. This ensures that mitochondria locate in proximity to every myofibril. Notably, antiparallel microtubules bundle with the assembling myofibrils, suggesting a key role in myofibril orientation. Indeed, microtubule severing affects myofibril orientation, whereas kinesin knockdown specifically blocks mitochondria intercalation. Importantly, mitochondria intercalation and their kinesin-dependent microtubule-based transport are conserved in mammalian muscle. Together, these data identify a key role for microtubules in coordinating mitochondria and myofibril morphogenesis to build functional muscles.

Keywords:  Drosophila; development; kinesin; live imaging; microtubules; mitochondria; mouse; muscle; myofibrillogenesis; sarcomere

DOI:  https://doi.org/10.1016/j.devcel.2025.06.033
Epigenomics. 2025 Jul 20. 1-8

The emerging role of multiomics in aging research.

Douglas M Ruden.

  Aging is a complex biological process involving coordinated changes across multiple molecular systems. Traditional reductionist approaches, while valuable, are insufficient to capture the full scope of aging's systemic nature. Multiomics - integrating data from genomics, transcriptomics, epigenomics, proteomics, and metabolomics - provides a comprehensive framework to study aging as an interconnected network. In this Perspective, I explore how multiomic strategies, particularly those leveraging epigenomic and single-cell data, are reshaping our understanding of aging biology. Epigenetic alterations, including DNA methylation and histone modifications, are not only hallmarks but also powerful biomarkers of biological age. I discuss advances in multiomic aging clocks, cross-tissue atlases, and single-cell spatial technologies that decode aging at unprecedented resolution. I also build on a prior review I wrote with colleagues, Epigenomics. 2023;15(14):741-754, which introduced the concept of pathological epigenetic events that are reversible (PEERs) - epigenetic alterations linked to early-life exposures that predispose to aging and disease but may be therapeutically modifiable. This Perspective examines how PEERs and multiomics intersect to inform biomarkers, geroprotective interventions, and personalized aging medicine. Finally, I highlight integration challenges, ethical concerns, and the need for standardization to accelerate clinical translation. Together, these insights position multiomics as a central pillar in the future of aging research.

Keywords:  DNA methylation; Multiomics; epigenomics; epitranscriptomics; hallmarks of aging and DOHaD; healthspan; histone modifications; lifespan

DOI:  https://doi.org/10.1080/17501911.2025.2533111