bims-moremu 2026-01-25 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–01–25
33 papers selected by
Anna Vainshtein, Craft Science Inc.

Efficacy of neonatal mouse muscle extracellular vesicles in skeletal muscle repair and regeneration.
Impact of exercise-induced DNA damage repair on age-related muscle weakness and sarcopenia.
Carbs vs. fats: Who takes first in skeletal muscle signalling?
ASB5 is a specific marker for muscle satellite cells but dispensable for skeletal muscle development and regeneration.
Functional role of THRAP3 in modulating thyroid hormone-mediated gene networks in C2C12 myotubes.
Roles of DRP1 and the fission protein interactome as regulators of cellular stability and sarcopenia in skeletal muscle aging.
The role of AGEs in skeletal muscle atrophy and the beneficial effects of exercise.
Histopathology and spatial transcriptomics jointly map myofiber-specific pathological programs in mTORC1-driven myopathy.
miRNA-206 in crosstalk muscle and central nervous system pathophysiology during exercise: a double-edged sword with therapeutic potential.
Differential regulation of mitochondrial quality control in skeletal muscle by HZE radiation exposure and partial weightbearing in mice.
Fiber-type-specific architecture and pathophysiology of the neuromuscular junction.
Optineurin binding to the novel interacting partner Junction plakoglobin prevents muscle atrophy in mice.
The contribution of skeletal muscle interstitial cells to myogenesis.
Identification of skeletal muscle stem cell adhesion motifs using spot-synthesis-based peptide arrays.
Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but not histological features of Duchenne muscular dystrophy in mice.
Distinct Myogenic Stages Recapitulate Transcriptomic Networks in COPD Cachexia.
Isoform-specific structure and function of calsequestrin: Implications beyond calcium buffering in health and disease.
Pathogenesis and risk factors of sarcopenia.
Exploring molecular signatures in PURA syndrome using muscle proteomics and serum biomarkers.
METTL16-m6A-PGC-1α axis contributes to exercise-induced mitochondrial adaptations in skeletal muscle of high-fat diet-fed insulin-resistant mice.
Versatile role of fibro-adipogenic progenitors in neuromuscular junction homeostasis and pathology.
Mechanisms of Skeletal Muscle Mass Regulation and Muscle Memory.
Skeletal muscle-specific PGC-1α-b overexpression prevents eccentric contraction-induced muscle injury through an utrophin-independent pathway in mice.
ERLIN2-Ca2+-CREB signaling coordinates circadian timing via CRY1/CRY2 feedback.
Systemic Phosphate Elevations Induce FGF23 Production in Skeletal Muscle to Reduce Renal Phosphate Reabsorption in Mice.
Advancing treatment of spinal muscular atrophy through inhibition of the myostatin signaling pathway.
Vitamin B12 supports skeletal muscle oxidative phosphorylation capacity in male mice.
Integrating SMRT and Bulk RNA Sequencing With Metabolic Phenotyping to Examine Reduced Skeletal Muscle Mitochondrial Respiration in Type 2 Diabetes.
Distinct Metabolomic Alterations Are Associated With Physical Function, Weight Loss, and Muscle Mass in Men With Cancer.
Dietary polyphenols and sarcopenia: epigenetic mechanisms and geroscience perspectives for muscle health in aging.
The Myokine FGF-21 Responds in a Time-Dependent Manner to Three Different Types of Acute Exercise.
Age and sex shape plasma lipid associations to skeletal muscle mitochondrial respiration and H2O2 emission.
A review of omics studies in sarcopenia: from molecular mechanisms to hepatic-gut-muscle interactions in chronic liver disease comorbidity.

Cell Regen. 2026 Jan 23. 15(1): 6

Efficacy of neonatal mouse muscle extracellular vesicles in skeletal muscle repair and regeneration.

Chengwei Liu, Zhouyan Li, Xinyue Liu, Sitong Lv, Xijun Yin.

  Currently, effective treatments for skeletal muscle injury remain limited. The self-repair of skeletal muscle relies on the activation and differentiation of satellite cells (SCs), which fuse with damaged myofibers to form new fibers and thereby support muscle regeneration. However, in cases of severe injury, it is difficult for muscle tissue to fully restore its original structure and function, and its regenerative capacity is often markedly reduced. Thus, there is an urgent need to develop therapies that enhance muscle repair and restore physiological function. In this study, we investigated extracellular vesicles derived from neonatal mouse skeletal muscle (NMM-EVs), which are enriched in cargo from Pax7⁺ myogenic progenitor cells. We hypothesized that NMM-EVs could enhance SC activation and improve muscle regeneration following injury. Using glycerol-induced tibialis anterior (TA) muscle injury model, we evaluated the effects of intramuscular NMM-EV administration on skeletal muscle regeneration by histological, immunofluorescence, and functional analyses. In vivo, NMM-EVs significantly promoted skeletal muscle regeneration and functional recovery, upregulated Pax7 expression, increased the cross-sectional area and muscle mass of regenerated TA, and reduced fibrosis and fat infiltration. In vitro, NMM-EVs enhanced the proliferation and myogenic differentiation of mouse SCs and increased the expression of myogenic regulatory factors at both the mRNA and protein levels. In conclusion, this study demonstrates that NMM-EVs activate SCs within injured muscle, promote their proliferation and differentiation, and thereby accelerate injury repair and myofiber regeneration while attenuating fibrotic and adipogenic remodeling. These findings provide a scientific basis for the development of neonatal muscle-derived extracellular vesicle-based, cell-free therapeutic strategies for skeletal muscle injury.

Keywords:  Extracellular vesicles-based therapy; Glycerol-induced injury; Muscle regeneration; Neonatal mouse muscle extracellular vesicles; Satellite cell

DOI:  https://doi.org/10.1186/s13619-025-00274-6
Front Genet. 2025 ;16 1639224

Impact of exercise-induced DNA damage repair on age-related muscle weakness and sarcopenia.

Lingyan Zhu, Yiping Su, Zhanguo Su.

  Sarcopenia, the progressive and generalized loss of skeletal muscle mass, strength, and function with aging, poses a significant public health challenge. A key contributor to sarcopenia is the accumulation of DNA damage, both nuclear and mitochondrial, coupled with a decline in DNA repair efficiency. This genomic instability, exacerbated by chronic oxidative stress and inflammation, impairs critical cellular processes including protein synthesis, mitochondrial function, and satellite cell regenerative capacity, ultimately leading to myofiber atrophy and weakness. Intriguingly, regular physical exercise, while acutely inducing transient DNA damage, concurrently activates and enhances DNA damage repair pathways, serving as a powerful physiological modulator of genomic integrity. This review comprehensively explores the intricate interplay between exercise, DNA damage, and DNA repair in the context of age-related muscle decline. We delve into the molecular hallmarks of DNA damage (e.g., 8-OHdG, SSBs, DSBs) and the major repair mechanisms (BER, NER, MMR, HR, NHEJ), detailing how acute exercise modalities (e.g., high-intensity interval training, resistance training) induce specific damage types primarily via reactive oxygen species. Crucially, we synthesize emerging evidence suggesting that chronic exercise training may upregulate the efficiency and capacity of DNA repair enzymes, particularly OGG1 in base excision repair, thereby mitigating the accumulation of deleterious genomic lesions. This exercise-induced enhancement of DNA repair directly contributes to maintaining mitochondrial health, preserving muscle stem cell function, and combating cellular senescence and inflammation, ultimately delaying or ameliorating sarcopenia and improving muscle functional outcomes in older adults. We highlight critical gaps in understanding the precise modulation of all repair pathways by exercise and propose future research directions, including advanced biomarker development and personalized exercise prescriptions, to harness the therapeutic potential of DNA repair for healthy muscle aging.

Keywords:  DNA damage repair; aging; exercise; physical activtiy; sarcopenia

DOI:  https://doi.org/10.3389/fgene.2025.1639224
J Physiol. 2026 Jan 20.

Carbs vs. fats: Who takes first in skeletal muscle signalling?

Sean Killip.



Keywords:  carbohydrate metabolism; cell signalling; exercise metabolism; lipid metabolism

DOI:  https://doi.org/10.1113/JP290564
Skelet Muscle. 2026 Jan 19.

ASB5 is a specific marker for muscle satellite cells but dispensable for skeletal muscle development and regeneration.

Muhammad Asif, Stephanie N Oprescu, Renjie Shang, Zheng Zhang, Feng Yue, Pengpeng Bi, Shihuan Kuang.

   BACKGROUND: Skeletal muscle plays a crucial role in human life, contributing to posture, movement, nutrient storage, and body temperature regulation. Development and regeneration of skeletal muscles rely on embryonic myogenic progenitors and postnatal satellite cells (MuSCs), respectively. Identification of new molecular markers and elucidating their functions in MuSCs will provide better understanding of muscle development and regeneration.
METHODS: We surveyed single cell RNA-seq (scRNA-seq) data (Tabula Muris and GSE150366) to identify ASB5 (Ankyrin repeat and Suppressor of cytokine signaling Box containing 5) as a marker of MuSCs. We also used CRISPR-CAS9 genome editing and oviduct electroporation to generate a germline knockout (KO) mouse line of Asb5. We then analyzed the muscle growth and regeneration of the KO mice. We further analyzed proliferation and differentiation of MuSCs attached on myofibers. We finally performed Realtime PCR (qPCR) to examine how Asb5 KO affects gene expression in the skeletal muscle.
RESULTS: Analysis of data publicly available at Tabula Muris identified Asb5 as a specific marker of MuSCs. Further analysis of scRNA-seq data on FACS-purified MuSCs at various regeneration time points revealed that Asb5 is highly expressed in MuSCs and their progenies across various stages of muscle regeneration. We then generated a novel Asb5 KO mouse line through CRISPR-Cas9 deletion of Exon 4. The Asb5-KO mice were born normally and exhibited normal postnatal growth. In addition, Asb5-KO MuSCs proliferated, differentiated and self-renewed normally on myofiber explants. Furthermore, the skeletal muscles of Asb5-KO mice regenerated normally after acute injury. qPCR analysis showed that Asb5 KO reduces the expression levels of Tnfa (Tumor Necrosis Factor Alpha) in the skeletal muscles.
CONCLUSION: These data together identify ASB5 as an abundantly expressed and specific marker of MuSCs and myogenic progenitors. However, Asb5 loss-of-function has no effects on embryonic development and postnatal growth of skeletal muscles, or behavior and regenerative functions of MuSCs under normal physiological conditions.

Keywords:   Asb5 ; CRISPR/Cas9; Myogenesis; Regeneration; Satellite cell; Skeletal muscle

DOI:  https://doi.org/10.1186/s13395-025-00409-y
PLoS One. 2026 ;21(1): e0341353

Functional role of THRAP3 in modulating thyroid hormone-mediated gene networks in C2C12 myotubes.

Taku Fukushima, Sachi Kuse, Yuka Hasegawa, Taiju Fujioka, Takeshi Nikawa, Satoru Masubuchi, Iori Sakakibara.

Thyroid hormone (TH) secreted by the thyroid gland plays essential roles in regulating metabolism, development, and nervous system function. Thyroid hormone receptor-associated protein 3 (THRAP3) is a nuclear coactivator that interacts with the thyroid hormone receptor (TR) and facilitates target gene regulation through the mediator complex. Although this mechanism has been well studied in other tissues, the specific role of THRAP3 in skeletal muscle remains unclear. Here we investigated the function of THRAP3 in skeletal muscle using Thrap3 knockout (KO) C2C12 cells. Loss of THRAP3 significantly suppressed the expression of key myogenic regulatory factors, including Myod1, Mef2c, and myosin heavy chain genes, resulting in impaired myogenic differentiation and muscle diameter. Furthermore, we found that THRAP3 influences triiodothyronine (T3)-induced gene expression, suggesting that it cooperatively modulates thyroid hormone signaling in muscle cells. Taken together, our findings identify THRAP3 as a novel regulator of myogenesis and indicate that it supports T3 activity by coordinating thyroid hormone-responsive gene expression in skeletal muscle.

DOI: https://doi.org/10.1371/journal.pone.0341353
Aging Adv. 2025 Dec 18.

Roles of DRP1 and the fission protein interactome as regulators of cellular stability and sarcopenia in skeletal muscle aging.

C Nivedya, Prasanna Venkhatesh, Benjamin I Rodriguez, Han Le, Jeremiah Afolabi, Andrea Marshall, Kit Neikirk, Sepiso K Masenga, Muhammad Aftab, Leo Jake Kazma, Prasanna Katti, Antentor Hinton.

  Mitochondrial function is crucial in regulating cellular activity and determining cell fate. The replication and transcription of mitochondrial DNA are essential for maintaining mitochondrial integrity. These processes are governed by mitochondrial fission and fusion, which play a vital role in energy distribution, quality control, and metabolic regulation. Mitochondrial fission relies on the coordinated actions of mitochondria-endoplasmic reticulum contact sites, actin filaments, and dynamin-related protein 1, which collectively mediate mitochondrial constriction and fission. This interplay is fundamental to mitochondrial homeostasis and, critically, to the functionality of skeletal muscle. In this review, we explore the complex interactions among dynamin-related protein 1, mitochondria-endoplasmic reticulum contact sites, and actin and their significance for skeletal muscle function. Additionally, we discuss potential strategies to preserve these interactions, supporting optimal muscle performance in skeletal muscle aging. This review provides key insights and outlines future research directions to advance our understanding of this essential yet widely studied relationship.

Keywords:  dynamin-related protein 1 (DRP1); exercise interventions; fission and fusion; mitochondria quality control; mitochondrial dynamics; mitochondria–endoplasmic reticulum contact sites (MERCs); mitophagy; posttranslational modifications; sarcopenia; skeletal muscle aging

DOI:  https://doi.org/10.4103/agingadv.agingadv-d-25-00013
Front Med (Lausanne). 2025 ;12 1626570

The role of AGEs in skeletal muscle atrophy and the beneficial effects of exercise.

Xinru Wu, Shuai Hu, Wei Miao, Fei Shen, Li Jiang.

   Background: Advanced Glycation End Products (AGEs) are associated with the aging and atrophy of skeletal muscle. Their pathogenic mechanism mainly involves the binding of AGEs to their own receptors, which in turn triggers a series of pathological reactions. Exercise is considered an effective intervention method, as it can regulate the level of AGEs, thereby alleviating skeletal muscle atrophy.
Objective: This study aims to review the latest research progress on skeletal muscle atrophy induced by AGEs and the beneficial effects of exercise.
Methods: Relevant literature was searched from the establishment of databases (PubMed, Web of Science, Embase, and Scopus) to May 2025. The search terms were: "advanced glycation end products, receptor for advanced glycation end products, skeletal muscle, skeletal muscle atrophy, sarcopenia, aging, diabetes mellitus, obesity, exercise, aerobic training, resistance training, high-intensity interval training". Literature was included based on the following criteria: (a) Studies focusing on the mechanism of skeletal muscle atrophy induced by AGEs and the content related to exercise regulating AGEs levels; (b) Priority was given to literature published in the past 5 years with outstanding quality, relevance, or innovation. Finally, 138 pieces of literature were included for the review.
Results and conclusions: AGEs bind to the receptor for advanced glycation end products (RAGE), which leads to a decrease in muscle protein synthesis, an increase in protein degradation, impairment of muscle fiber regeneration ability, and aggravation of myocyte apoptosis, thereby inducing or exacerbating skeletal muscle atrophy. Exercise can reduce the harmful effects of AGEs on muscle mass. Specifically, exercise can reduce the formation of AGEs by improving insulin sensitivity and glucose utilization, as well as alleviating chronic inflammation and oxidative stress. Additionally, exercise enhances the metabolic capacity of the kidneys for AGEs. These findings provide new insights for the development of drug regimens targeting the "AGEs-RAGE" axis and exercise interventions. In the future, in-depth clarification of the role of AGEs in the pathogenesis of skeletal muscle atrophy and the improvement mechanism mediated by exercise will provide an important basis for the prevention and treatment of sarcopenia related to aging and metabolic disorders.

Keywords:  AGEs-RAGE signaling axis; advanced glycation end-products; aging; exercise; inflammation; mitochondria; oxidative stress; skeletal muscle atrophy

DOI:  https://doi.org/10.3389/fmed.2025.1626570
bioRxiv. 2025 Dec 07. pii: 2025.12.03.692123. [Epub ahead of print]

Histopathology and spatial transcriptomics jointly map myofiber-specific pathological programs in mTORC1-driven myopathy.

Jer-En Hsu, Qingyang Zhao, Weiqiu Cheng, Hyun-Min Kang, Susan V Brooks, Myungjin Kim, Jun Hee Lee.

Skeletal muscle is a structurally organized and functionally diverse organ composed of heterogeneous myofiber types and supporting non-myocyte populations that act in concert to generate force, regulate metabolism, and maintain systemic homeostasis. Myopathies occur in many different diseases, but the mechanisms that drive these muscle pathologies are still largely unknown, partly because conventional approaches cannot link histopathological features to molecular states at single-fiber resolution. To address this challenge, we brought histopathology and spatial transcriptomics together by applying high-resolution Seq-Scope technology to a rodent model of mTORC1 hyperactivation, which produces diverse pathological alterations within individual myofibers. Cross-sections from extensor digitorum longus (EDL) and soleus (SOL), two muscles with distinct fiber-type compositions, were profiled to determine how transcriptome changes are linked to histopathological outcomes. Our analyses reveal that mTORC1 hyperactivation elicits distinct, fiber-type-dependent pathological programs. Type I and IIa fibers, abundant in SOL but scarce in EDL, were largely resistant to mTORC1-induced pathology, exhibiting only minimal morphological alterations and no fiber type-specific responses beyond those commonly observed throughout the tissue. In contrast, type IIx fibers, shared between both muscles, diverged into opposing fates: in SOL, they underwent abnormal enlargement driven by sustained growth signaling, cytoskeletal remodeling, and impaired proteostasis with defective autophagy; whereas in EDL, they developed basophilia characterized by lipid-supported respiration fueling excessive ribonucleotide synthesis and RNA accumulation. Within the same muscle, type IIb fibers displayed striking heterogeneity with discrete transcriptional states encompassing canonical stress responses, oxidative metabolic activation, and developmental reprogramming. In parallel, non-myocytic populations, including activated macrophages and fibroblasts, accumulated preferentially in SOL, forming a fibrotic microenvironment supporting inflammation, tissue remodeling and hypertrophy. Taken together, these findings reveal that sustained mTORC1 signaling disrupts muscle homeostasis through distinct metabolic and structural routes, directly linking histopathological phenotypes to their molecular states at single-fiber resolution.

DOI: https://doi.org/10.64898/2025.12.03.692123
Neurosci Biobehav Rev. 2026 Jan 20. pii: S0149-7634(26)00024-2. [Epub ahead of print] 106569

miRNA-206 in crosstalk muscle and central nervous system pathophysiology during exercise: a double-edged sword with therapeutic potential.

Amir Mohammad Malvandi, Laura Gerosa, Paola Maroni, Maria Emanuela Orlando, Abbas Mohammadipour, Giovanni Lombardi.

  Physical activity triggers complex molecular responses in skeletal muscle, with increasing evidence showing systemic signaling roles for muscle-derived microRNAs (myomiRs). Among these, miR-206 has attracted attention for its dual function: promoting muscle regeneration but potentially harming the central nervous system (CNS). This review examines how miR-206 expression is regulated during exercise and its effects on muscle biology-such as fiber-type specification, mitochondrial changes, and neuromuscular junction (NMJ) repair. It also explores the paradoxical effects of high miR-206 levels in the CNS, where it targets brain-derived neurotrophic factor (BDNF), reducing neuroplasticity and increasing vulnerability to neuropsychiatric and neurodegenerative diseases. The review highlights disease-specific aspects, showing miR-206 as harmful in Alzheimer's, stroke, and depression, but potentially protective in amyotrophic lateral sclerosis (ALS). We discuss its potential as a biomarker and therapeutic target, stressing tissue-specific regulation approaches. Overall, miR-206 plays a key role in muscle-brain communication, with important implications for exercise, aging, and CNS disorders.

Keywords:  Exercise; Muscle damage; Neurodegeneration; miR-206; muscle–brain crosstalk, BDNF

DOI:  https://doi.org/10.1016/j.neubiorev.2026.106569
Life Sci Space Res (Amst). 2026 Jan;pii: S2214-5524(25)00127-0. [Epub ahead of print]48 156-165

Differential regulation of mitochondrial quality control in skeletal muscle by HZE radiation exposure and partial weightbearing in mice.

Carla Mc Nascimento, James D Fluckey, Florence Lima, Brandon R Macias, Yasaman Shirazi-Fard, Elizabeth S Greene, Leslie A Braby, Susan A Bloomfield, Michael P Wiggs.

  Spaceflight places astronauts under both reduced mechanical loading and ionizing radiation, each of which can compromise skeletal muscle health. We investigated whether 21 days of simulated lunar gravity (one sixth G) with or without a single 0.5 Gy dose of 28Si heavy ion radiation alters transcriptional regulators of mitochondrial quality control in mouse gastrocnemius muscle. Female BALB/cByJ mice were assigned to four groups: Sham + 1 G (SHAM+CC), Rad + 1 G (RAD+CC), Sham + G/6 (SHAM+G/6), Rad + G/6 (RAD+G/6) and relative mRNA levels of key regulators of mitochondrial biogenesis, mitophagy, dynamics and electron transport chain content were measured by quantitative RT-PCR. Radiation significantly suppressed PGC-1α (p = 0.035) and TFAM (p = 0.051) transcripts and reduced LC3b (p = 0.033) and Park2 (p = 0.007) expression; no effects of simulated lunar gravity or interaction effects were detected. Composite scores confirmed suppression of biogenesis (p = 0.029) and a trend toward reduced mitophagy (p = 0.057). Transcripts encoding oxidative phosphorylation subunits and fusion and fission factors remained unchanged, suggesting preserved mitochondrial content and network homeostasis at day 21. These findings indicate that a single space relevant heavy ion exposure selectively disrupts early transcriptional steps of mitochondrial turnover without immediately altering organelle abundance of transcripts for electron transport chain or dynamics; in contrast simulated lunar gravity alone did not elicit changes in these pathways.

Keywords:  Autophagy; Biogenesis; Dynamics; Fission; Fusion; Spaceflight

DOI:  https://doi.org/10.1016/j.lssr.2025.10.008
Neuroscience. 2026 Jan 16. pii: S0306-4522(26)00039-4. [Epub ahead of print]

Fiber-type-specific architecture and pathophysiology of the neuromuscular junction.

Rizwan Qaisar.

  The neuromuscular junction (NMJ) is a specialized synapse essential for translating neuronal signals into muscle contraction. This review examines the complex structural, functional, and molecular differences in NMJs that innervate fast- and slow-twitch skeletal muscle fibers. Fast-twitch fibers, optimized for rapid and powerful contractions, possess elaborate NMJs with deep folds, high neurotransmitter turnover, and greater vulnerability to synaptic fatigue and degeneration. In contrast, slow-twitch fiber NMJs exhibit simpler but more stable architectures that support sustained, fatigue-resistant activity. These differences are not fixed but subject to activity-dependent plasticity and pathological remodeling. Chronic stimulation, injury, and aging influence NMJ morphology, with fast-twitch junctions more prone to degeneration in conditions such as ALS, myasthenia gravis, and diabetic neuropathy. Slow-twitch NMJs often resist early deterioration due to superior trophic support, metabolic stability, and more robust expression of synaptic organizers, such as agrin and PGC-1α. Several key signaling pathways, including agrin-MuSK-LRP4, Wnt/β-catenin, and neuregulin/ErbB, govern NMJ maintenance with fiber-type-specific nuances. These insights underscore the importance of tailoring therapeutic strategies to the muscle fiber phenotype. Gene therapies, neuromuscular electrical stimulation, and biomaterial scaffolds are emerging as promising modalities for preserving or restoring NMJ integrity, especially in fast-twitch fibers at higher risk of degeneration. Understanding fiber-type-specific NMJ biology enhances our understanding of motor control, muscle aging, and neuromuscular disease progression, and it opens pathways for precision therapeutics that target vulnerable synapses with structural and functional specificity. This review introduces a novel perspective by emphasizing fiber-type-specific NMJ differences and their implications for targeted therapies.

Keywords:  Ageing; Muscle fiber types; Neuromuscular junction

DOI:  https://doi.org/10.1016/j.neuroscience.2026.01.015
PLoS Biol. 2026 Jan 22. 24(1): e3003581

Optineurin binding to the novel interacting partner Junction plakoglobin prevents muscle atrophy in mice.

Xiao Chen Shi, Rui Xin Zhang, Jun Kai Feng, Jia Hao Chen, Jian Feng Zhang, Jun Ying Xiao, Xiao Peng Liu, Huan Liu, Bo Xia, Li Nong Yao, Jiang Wei Wu.

Skeletal muscle atrophy is a debilitating condition that significantly affects patients' quality of life and prognosis, yet its underlying mechanisms remain poorly understood. Here, we identify Optineurin (OPTN) as an active regulator for maintenance of muscle homeostasis during muscle atrophy. Knockdown (KD) of Optn induces muscle atrophy, while overexpression of Optn alleviated dexamethasone-induced muscle atrophy in mice. Mechanistically, we for the first time identified Junction plakoglobin (JUP) as a novel interacting partner of OPTN. OPTN alleviates muscle atrophy in a JUP-dependent manner, corroborating JUP as the downstream effector of OPTN-mediated muscle atrophy. RNA-seq analysis revealed that PI3K-AKT pathway is markedly downregulated in Optn-KD muscle, and pharmacological activation of PI3K-AKT pathway effectively rescued muscle atrophy in Optn-KD mice. We further show that OPTN coordinates the interaction between JUP and PI3-Kinase p85 in muscle, promoting activation of the PI3K-AKT pathway. Collectively, our study proposed a conceptual novelty that OPTN-JUP axis mediated activation of the PI3K-AKT pathway during muscle atrophy. These findings offer new insights into the mechanisms of muscle atrophy and suggest potential therapeutic strategies for this condition.

DOI: https://doi.org/10.1371/journal.pbio.3003581
Skelet Muscle. 2026 Jan 21.

The contribution of skeletal muscle interstitial cells to myogenesis.

Fayez Issa, Frédéric Relaix, Joana Esteves de Lima.



Keywords:  Connective tissue; Development; FAPs; Myogenesis; Regeneration

DOI:  https://doi.org/10.1186/s13395-026-00414-9
iScience. 2026 Jan 16. 29(1): 114498

Identification of skeletal muscle stem cell adhesion motifs using spot-synthesis-based peptide arrays.

Elizabeth Leblanc, Svenja C Schüler, Yuguo Liu, Léa Théroux, Emmeran Le Moal, Marc-André Bonin, Pierre-Luc Boudreault, C Florian Bentzinger.

  Altered interactions with the extracellular matrix (ECM) represent a root cause of skeletal muscle stem cell (MuSC) dysfunction in aging and disease, underscoring the therapeutic potential of targeting adhesion receptors. Here, we describe the development of an approach for the medium-throughput screening of bioactive ECM-derived adhesion motifs using peptide arrays generated by highly parallel SPOT synthesis. Based on a library of ∼50 peptide sequences originating from ECM proteins, we identified several candidate motifs that robustly enhance the adhesion of MuSC-derived cells. We demonstrate that these peptide motifs can improve the in vitro phenotype of MuSC-derived cells isolated from dystrophic muscle and provide proof-of-concept that they can be chemically modified for efficient bioconjugation, in vivo basal-lamina-binding, and as receptor-targeting molecular probes. Altogether, our work provides a versatile toolkit for studying MuSC adhesion and uncovers a set of functional peptide motifs with translational potential for pro-regenerative therapies in skeletal muscle disorders.

Keywords:  Biotechnology; Cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.114498
Sci Rep. 2026 Jan 17.

Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but not histological features of Duchenne muscular dystrophy in mice.

Olivier Reynaud, Marie-Belle Ayoub, Jean-Philippe Leduc-Gaudet, Marina Cefis, Marc P Lussier, Sabah Na Hussain, Gilles Gouspillou.

Duchenne Muscular Dystrophy (DMD) is the most common childhood muscular disorder. Mitochondrial dysfunctions are key disease features of the disease, and strategies that improve mitochondrial health have emerged as promising to slow disease progression. Emerging evidence indicates that impaired/insufficient mitophagy may contribute to the accumulation of mitochondrial dysfunction seen in patients and animal models of DMD. We therefore hypothesized that overexpressing Parkin, a key mitophagy regulator, may improve mitochondrial and muscle health in a mouse model of DMD. To this end, Parkin was overexpressed using intramuscular injections of adeno-associated viruses performed in 5-week-old and 18-week-old D2.B10-Dmdmdx/J mice (D2.mdx), a widely used mouse model of DMD. Four and 16 weeks of Parkin overexpression initiated in 5-week-old and 18-week-old D2.mdx, respectively, resulted in muscle hypertrophy, as indicated by an increase in muscle mass and fiber cross-sectional area. While Parkin overexpression did not impact maximal mitochondrial respiration or mitochondrial content, it increased the Acceptor Control Ratio, an index of mitochondrial bioenergetic efficiency. Parkin overexpression also decreased mitochondrial H2O2 emission, a surrogate for mitochondrial ROS production. However, Parkin overexpression failed to reduce the proportion of fibers with central nuclei and markers of muscle damage and/or necrosis. Taken all together, our results indicate that Parkin overexpression can attenuate muscle atrophy, improve mitochondrial bioenergetics and lower mitochondrial ROS production in a mouse model of DMD. These findings showcase the partial beneficial effects of overexpressing Parkin in ameliorating some, but not all, pathological features observed in a mouse model of DMD.

DOI: https://doi.org/10.1038/s41598-025-34223-9
bioRxiv. 2025 Dec 05. pii: 2025.12.03.692216. [Epub ahead of print]

Distinct Myogenic Stages Recapitulate Transcriptomic Networks in COPD Cachexia.

Hanna Sothers, Bitota Lukusa-Sawalena, Kaleen M Lavin, Wenxia Ma, Joe W Chiles, Richard Casaburi, Rakesh Patel, J Michael Wells, Mohamed Kazamel, Harry B Rossiter, Anna Thalacker-Mercer, Merry-Lynn N McDonald.

Background: Cachexia is an extrapulmonary manifestation of Chronic Obstructive Pulmonary Disease (COPD) characterized by weight loss and muscle wasting. Transcriptomic profiling of vastus lateralis biopsies enables profiling of COPD-cachexia relevant dysregulation. As obtaining muscle biopsies is invasive and yields limited tissue, human muscle derived cultures (HMDC) may enable mechanistic research into cachexia. However, questions remain regarding the extent to which HMDC recapitulate transcriptomic signatures of bulk skeletal muscle in COPD-cachexia. To address this gap, we tested whether COPD and COPD-cachexia associated transcriptional dysregulation signatures in bulk skeletal muscle are preserved in derived myoblasts, myocytes, and myotubes.
Methods: Vastus lateralis biopsies were collected from 13 (6M/7F, 64±9 years) participants; COPD n=5, COPD-cachexia n=4, and 4 age-matched controls. Cachexia was defined using a composite measure of weight loss coupled with reduced muscle strength, fatigue, anorexia, low muscle mass and/or systemic inflammation. Satellite cells were isolated and differentiated into myoblasts, myocytes, and myotubes. Differential gene expression testing, generated from RNA-sequencing, identified transcripts significantly dysregulated (p>0.05) in bulk tissue. Weighted gene co-expression network analysis (WGCNA) was performed to identify modules of co-expressed genes at the whole-transcriptome and mitochondrial transcriptome levels. Bulk tissue modules were tested for preservation in HMDC (Z-summary >2) and correlated with clinical traits. Gene set enrichment analysis was performed for all modules.
Results: 1,379 genes were significantly differentially expressed in bulk samples from all COPD participants compared to controls. The top upregulated gene was IL32 (L2FC=4.5, p=1.3×10 - 3 ) and top downregulated CGN (L2FC=-5.8, p=8.8×10 - 3 ). A total of 632 genes were significantly differentially expressed in bulk samples from COPD participants with and without cachexia. The top upregulated gene was SEMA4F (L2FC=5.0, p=6.9×10 - 4 ) and top downregulated ARC (L2FC=-4.9, p=3.1×10 - 2 ). WGCNA generated 9 modules (Modules 1 - 9) at the whole-transcriptome level and 2 modules (Modules A and B) at the mitochondrial transcriptome level. Modules 1, 4, 5, and 9 were significantly correlated with COPD-cachexia. Of these, module 1 was preserved in myoblasts and modules 4, 5 and 9 in myocytes. These modules are enriched with genes involved in metabolic and inflammatory remodeling, catabolic stress and atrophy, and chromatin-driven regeneration.
Conclusions: These results provide a foundation for using myocytes and myoblasts as in vitro models of degeneration and repair pathway dysregulation in COPD-cachexia. Several modules were preserved between bulk skeletal muscle and HMDC, suggesting HMDC have utility for studying COPD-cachexia.

DOI: https://doi.org/10.64898/2025.12.03.692216
Cell Calcium. 2026 Jan 11. pii: S0143-4160(26)00013-8. [Epub ahead of print]134 103120

Isoform-specific structure and function of calsequestrin: Implications beyond calcium buffering in health and disease.

Punyadhara Pani, Diya Aich, Barsha Priyadarshini Kar, M Shiwangi Giri, Gourabamani Swalsingh, Muthu Periasamy, Naresh Chandra Bal.

  Calsequestrin (CASQ) plays an important role in muscle contraction by buffering Ca2+ inside the sarcoplasmic reticulum (SR). Intriguingly, mammals express two CASQ isoforms encoded by separate genes with highly conserved protein structure. CASQ1 is mainly expressed in fast-twitch skeletal muscles; whereas CASQ2 predominates in slow-twitch muscles and heart. CASQ2 function is poorly defined in rhythmically beating heart where SR Ca2+-release is graded through Ca2+-induced Ca2+-release (CICR), compared to CASQ1 in skeletal muscle where Ca2+-release is all or none. A unique property of CASQ is that it can dynamically polymerize-depolymerize in Ca2+-concentration dependent manner. CASQ1 and CASQ2 not only differ in their polymerization properties but also interact with different RyR protein complexes at the junctional SR governing muscle fiber specific SR Ca2+-release. In recent years CASQ has gained renewed attention because mutations in CASQ1 and CASQ2 proteins cause cardiac and skeletal muscle disease, including malignant hyperthermia (skeletal muscle), cardiac arrhythmias and sudden cardiac death. Additionally studies have implicated that CASQ is more than a Ca2+-buffer and CASQ-dysfunction can affect mitochondrial function and Ca2+-entry via store operated Ca2+-entry. Therefore, the isoform specific functions of CASQ1 and CASQ2 in different striated muscles requires further investigation in the light of recent findings. This review explores what we have learned over last 30 years about CASQ and what gaps of knowledge still exist. Here, we discuss how structural divergence between CASQ1 and CASQ2, shape physio-pathological outcomes and highlight some of the recent findings that trigger renewed interest in CASQ proteins, including their role beyond Ca2+-buffering.

Keywords:  Calcium signaling; Calsequestrin; Muscle contraction; Ryanodine receptor; Sarcoplasmic reticulum; Skeletal and cardiac muscle

DOI:  https://doi.org/10.1016/j.ceca.2026.103120
Yi Chuan. 2026 Jan 20. 48(1): 26-45

Pathogenesis and risk factors of sarcopenia.

Xin-Ran Li, Yan-Han Feng, Zhi-Dan Xia.

  Sarcopenia is an age-related degenerative disease characterized by progressive loss of skeletal muscle mass and function, resulting severe clinical outcomes such as falls, disability, and increased all-cause mortality, thereby significantly reducing the quality of life in elderly population. With China's rapid demographic aging, sarcopenia is emerging as a critical public health challenge. In this review, we elaborate the pathogenesis of sarcopenia, identifying metabolic imbalance and cellular oxidative stress as major contributing factors to muscle degeneration. Also, this article indicates that life-style, physiological condition and genetic factors jointly influence the population susceptibility and progression of sarcopenia. On one hand, this article lists the non-genetic factors that accelerate the progression of sarcopenia; and on the other hand, it elaborates the role of multiple genes in maintaining muscle function, and the risk associations between genetic mutations and sarcopenia which has been revealed in studies from population cohort and animal models. Moreover, this article summarizes how epigenetic factors regulate muscle metabolism and aging, and comprehensively discusses the intervention effects and clinical limitations of treatment, nutritional support, and exercise therapy. We hope this review can provide a theoretical framework to advance both fundamental research and clinical strategies for sarcopenia prevention and management.

Keywords:  aging; genetic regulation; muscle function; pathogenesis

DOI:  https://doi.org/10.16288/j.yczz.25-107
J Neurol. 2026 Jan 23. 273(2): 94

Exploring molecular signatures in PURA syndrome using muscle proteomics and serum biomarkers.

Magdalena Mroczek, Corinna Preusse, Andreas Hentschel, Magdalena Chrościńska-Krawczyk, Michał Bielak, Adela Sobolewska, Adela Della Marina, Anisa Hila, Stanley Iyadurai, Florian Kraft, Venkatesh Kumar Chetty, David Muhmann, Tobias Ruck, Hans-Hilmar Goebel, Ulrike Schara-Schmidt, Vera Dobelmann, Basant Kumar Thakur, Werner Stenzel, Andreas Roos.

   BACKGROUND AND PURPOSE: Dominant PURA variants (encoding purine-rich element-binding protein A) cause a neurodevelopmental disorder with hypotonia, cognitive impairment, and variable neuromuscular symptoms. Clinical presentations and response to pyridostigmine, moreover, highlighted neuromuscular junction (NMJ) involvement. However, NMJ architecture, underlying molecular mechanisms, and potential minimally invasive biomarkers in PURA syndrome remain poorly characterized. This study aimed to profile PURA-related disease using integrated clinical, histological, ultrastructural, transcriptional, and protein analyses of skeletal muscle and blood.
METHODS: Ten genetically confirmed patients underwent detailed phenotyping with emphasis on congenital myasthenic syndrome (CMS)-like features. Quadriceps biopsy from one patient was analyzed by histology, immunohistochemistry, and electron microscopy. Protein profiling of muscle, serum, and extracellular vesicles (EVs) was performed by ELISA and mass spectrometry, with validation by qPCR.
RESULTS: In line with the recognized classification of PURA syndrome as a CMS subtype, our patients exhibited hypotonia, ptosis, ocular weakness, and myopathic facies, reflecting impaired neuromuscular transmission. Subtle vesicle accumulation and minor NMJ alterations suggest possible neuromuscular involvement in PURA syndrome. Muscle proteomics showed reduced PURA protein and dysregulation of transcriptional regulation, vesicle transport, extracellular matrix remodeling, and complement activation. qPCR confirmed POSTN and PHGDH upregulation among others. Serum analyses demonstrated elevated TSP4, identifying a promising candidate blood biomarker for PURA-associated NMJ dysfunction. EV proteomics revealed dysregulated immunoglobulins, complement components, and novel candidates including NOTCH2, TARSH, and PON1.
CONCLUSIONS: Pathogenic PURA variants may impair NMJ structure and vesicle homeostasis, potentially linking molecular and ultrastructural defects with clinical myasthenic features and pyridostigmine responsiveness. Proteomic analysis of skeletal muscle provides initial molecular insights into the consequences of dominant PURA variants in muscle tissue. The identification of TSP4 and extracellular vesicle-associated proteins as potential minimally invasive biomarkers provides a framework for biochemical monitoring of PURA syndrome.

Keywords:  Congenital myasthenic syndrome (CMS); Extracellular vesicles in neuromuscular diseases; Muscle proteomics; Periostin (POSTN); Target of Nesh-SH3 (TARSH); Thrombospondin-4 (TSP4)

DOI:  https://doi.org/10.1007/s00415-026-13621-7
BMC Biol. 2026 Jan 22.

METTL16-m6A-PGC-1α axis contributes to exercise-induced mitochondrial adaptations in skeletal muscle of high-fat diet-fed insulin-resistant mice.

Cong Chen, Cai Jiang, Qing Xiang, Yue Hu, Huijuan Wu, Chunxiu Huang, Huanghao Zhou, Ying Xu, Meijin Hou, Weilin Liu, Xiao Han.

   BACKGROUND: The dynamic change of N6-methyladenosine (m6A) modification on substrate RNA molecules plays a critical role in different biological processes and disease pathogenesis. Although the beneficial effects of exercise training (ET) on skeletal muscle insulin resistance (IR) are well-established, the contribution of RNA m6A modification in ET-related adaptations in high-fat diet (HFD)-induced IR remains unclear.
RESULTS: In this study, we show that exercise stimulation triggers a dynamic shift in skeletal muscle m6A modification levels during HFD consumption. As a key m6A methyltransferase, METTL16 was downregulated in HFD-fed mice and upregulated by ET at both the mRNA and protein levels. In vitro, METTL16 knockdown disrupted mitochondrial ultrastructure, reduced electron transport chain complex activities, and decreased the NAD+/NADH ratio, ATP content, and mitochondrial membrane potential, indicating impaired mitochondrial function. Concomitantly, METTL16 loss lowered m6A on PGC-1α mRNA, reducing its stability and protein abundance and blunting insulin signalling, whereas PGC-1α overexpression partially reversed these defects.
CONCLUSIONS: In conclusion, METTL16 functions as an exercise-responsive m6A methyltransferase that may modulate PGC-1α, mitochondrial function, and insulin-related signalling in HFD skeletal muscle, implicating the METTL16-m6A-PGC-1α axis in exercise-induced metabolic adaptations.

Keywords:  Exercise; Insulin resistance; METTL16; Mitochondrial function; PGC-1α

DOI:  https://doi.org/10.1186/s12915-026-02519-5
Biochem Biophys Res Commun. 2026 Jan 12. pii: S0006-291X(26)00049-5. [Epub ahead of print]800 153286

Versatile role of fibro-adipogenic progenitors in neuromuscular junction homeostasis and pathology.

Ruizhi Li, Jingtao Li, Shujuan Zou, Xing Yin.

  The neuromuscular junction (NMJ) is a specialized synapse that enables reciprocal signaling between motor nerves and muscle fibers. NMJ integrity is essential for muscle homeostasis, while retrograde signals from muscle also modulate nerve axon physiology. Nerve injury or neuromuscular diseases often result in functional deficits and histological changes. Fibro-adipogenic progenitors (FAPs) are muscle-resident multipotent mesenchymal cells, and a large body of research illustrated their role in muscle mass maintenance and regeneration. Recently, FAPs have been suggested to be responsive to NMJ perturbations. However, many questions remain, including how FAPs sense nerve injury and neuropathology; what factors drive their fate determination; and what effectors mediate their responses to NMJ impairments. In this review, we first provide a brief overview of NMJ structure and formation, then discuss the role of FAPs in NMJ homeostasis, nerve injury, and neuromuscular diseases. FAPs regulate NMJ development and regeneration via paracrine factor secretion, extracellular matrix modulation, and cellular interaction. Aberrantly activated FAPs drive pathological muscle fibrosis, fatty-infiltration, and ectopic bone formation. This comprehensive perspective of FAP-NMJ interactions will shed a new light on NMJ regeneration mechanisms and neuromuscular disease control.

Keywords:  Acetylcholine receptor; Extracellular matrix; Fibro-adipogenic progenitors; Nerve injury; Neuromuscular diseases; Neuromuscular junctions

DOI:  https://doi.org/10.1016/j.bbrc.2026.153286
Acta Physiol (Oxf). 2026 Feb;242(2): e70152

Mechanisms of Skeletal Muscle Mass Regulation and Muscle Memory.

Kristian Gundersen, Jo C Bruusgaard, Einar Eftestøl.

Changes in muscle mass and force are mainly related to changes in fiber size. In eukaryotes, DNA-content and cell size are generally correlated, suggesting the existence of a DNA-template limitation. This might be particularly important in the skeletal muscle fiber syncytia, which contain 30%-50% less DNA per cytoplasmic volume than most cells. Muscle fibers display a correlation between fiber size and myonuclear number, and genetically reducing the number reduces the size. Even so, the cytoplasmic volume per nucleus is larger in larger cells, demonstrating some flexibility in each nucleus' ability to "produce volume." De novo hypertrophy leads to accrual of myonuclei, which do not seem to be lost; the "extra" nuclei might serve as a mechanism for muscle memory. A complementary hypothesis is that muscle memory relies on each nucleus' ability to provide protein related to persistent/long-lasting epigenetic traces. A few epigenetically altered loci have been suggested, but there is currently no consensus between various studies as to which these are.

DOI: https://doi.org/10.1111/apha.70152
Physiol Rep. 2026 Jan;14(2): e70743

Skeletal muscle-specific PGC-1α-b overexpression prevents eccentric contraction-induced muscle injury through an utrophin-independent pathway in mice.

Azuma Naito, Nao Tokuda, Nao Yamauchi, Ayaka Niibori, Kazuma Okada, Koichi Himori, Yuki Ashida, Takashi Yamada.

  Slower oxidative fibers are more resistant to eccentric contraction (ECC)-induced muscle damage than fast-twitch glycolytic fibers, but the mechanisms remain unclear. This study investigated the roles of the exercise-inducible PGC-1α isoform PGC-1α-b and utrophin in protecting against ECC-induced damage. ECCs were induced by supramaximal electrical stimulation of the left triceps surae in C57BL/6N wild-type (WT), PGC-1α-b transgenic (Tg), utrophin knockout (Utrn KO), and PGC-1α-b Tg/Utrn KO mice. Although the proportion of fast-type myosin heavy chain (MyHC) IIb in the gastrocnemius muscle was modestly lower in PGC-1α-b Tg and PGC-1α-b Tg/Utrn KO mice than in WT and Utrn KO mice, MyHC IIb remained the predominant isoform. At 3 days post injury (dpi), WT and Utrn KO mice exhibited reduced maximum isometric torque (MIT), Evans blue dye (EBD) staining in MyHC IIb-positive fibers, and calpain-1 activation. In contrast, PGC-1α-b Tg and PGC-1α-b Tg/Utrn KO mice showed substantial MIT recovery at 1 dpi and minimal EBD uptake and calpain-1 activation at 3 dpi. PGC-1α-b Tg muscles also preserved excitation-contraction coupling proteins and displayed increased mitochondrial markers and integrin α7B expression. Together, our findings suggest that PGC-1α-b confers resistance to ECC-induced muscle damage through a Utrn-independent mechanism.

Keywords:  PGC‐1α‐b; damage resistance; eccentric contraction; fiber type; utrophin

DOI:  https://doi.org/10.14814/phy2.70743
FEBS Lett. 2026 Jan 23.

ERLIN2-Ca2+-CREB signaling coordinates circadian timing via CRY1/CRY2 feedback.

Yuwen Chen, Jiaxin Lin, Zongyou Zou, Zuo-Qin Yan, Ruizhe Qian, Chao Lu, Bingxuan Hua.

  Circadian regulation in peripheral cells depends on calcium dynamics, but the upstream mechanisms remain unclear. We identify endoplasmic reticulum lipid raft-associated protein 2 (ERLIN2) as a regulator of the peripheral clock. Knockdown and overexpression of ERLIN2 in C2C12 skeletal muscle cells show that ERLIN2 positively regulates cryptochrome circadian regulator 1/2 (CRY1/2) transcription and maintains rhythmicity. ERLIN2 regulates inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ release and activates the calcium/calmodulin-dependent protein kinase II (CaMKII)-mitogen-activated protein kinase (MAPK)-cAMP response element-binding protein (CREB) pathway. ATP induced IP3R-dependent Ca2+ transients, CREB phosphorylation, and Per1 expression, reshaping circadian rhythm, effects blocked by IP3R, Ca2+, or CaMKII inhibition. CRY1 enhances and CRY2 suppresses CREB signaling, establishing a feedback loop with ERLIN2. This ERLIN2-Ca2+-CREB-CRY1/2 axis couples membrane contact sites to circadian regulation. Impact statement This study reveals ERLIN2 as a key regulator linking calcium signaling to circadian rhythms, establishing an ERLIN2-Ca2+-CREB-CRY1/2 axis that advances understanding of cellular clock control.

Keywords:  CREB pathway; CRY1/CRY2 feedback; ERLIN2; calcium signaling; circadian rhythm

DOI:  https://doi.org/10.1002/1873-3468.70291
J Am Soc Nephrol. 2025 Dec 30.

Systemic Phosphate Elevations Induce FGF23 Production in Skeletal Muscle to Reduce Renal Phosphate Reabsorption in Mice.

Kylie Heitman, Qing Li, Abul Fajol, Matthew Denniff, Dungeng Peng, S Madison Thomas, Brian Czaya, Christopher Yanucil, David Westbrook, Syed Wasiuddin, Glenn C Rowe, Abolfazl Zarjou, Orlando M Gutierrez, Kenneth E White, Jorge L Gamboa, Emma L Watson, Matthew S Alexander, Christian Faul.

BACKGROUND: Fibroblast growth factor 23 (FGF23) is a hormone that reduces the renal reabsorption of phosphate in response to systemic phosphate elevations. In chronic kidney disease (CKD), serum levels of phosphate and FGF23 reach levels that can harm various tissues. While the bone acts as the main production site for FGF23, bone-specific gene deletion studies in mice suggest the existence of other FGF23 sources. Here, we determine if skeletal muscle produces FGF23 in response to phosphate elevations.
METHODS: We studied four mouse models with phosphate elevations, two with CKD (global Col4a3 deletion and adenine-rich diet) and two without CKD (genetic klotho deficiency and high-phosphate diet). Furthermore, we generated a new mouse line with skeletal muscle-specific Fgf23 deletion (KO), which received an adenine-rich or high-phosphate diet. We measured skeletal muscle FGF23 by qRT-PCR, ELISA, and immunohistochemistry as well as serum levels of phosphate, FGF23, and parathyroid hormone (PTH). We determined FGF23 mRNA levels in muscle biopsies from CKD patients, and we studied the effects of phosphate and PTH elevations on FGF23 expression in cultured myotubes isolated from mice and CKD patients. Finally, we studied the effects of acute phosphate loading on urine phosphate levels in Fgf23 KO mice.
RESULTS: All four mouse models with phosphate and PTH elevations showed FGF23 expression in skeletal muscle tissue on mRNA and protein level. Phosphate, but not PTH, induced FGF23 expression in cultured myotubes. Furthermore, CKD patients with higher serum phosphate levels expressed more FGF23 in skeletal muscle. Fgf23 KO mice had elevated serum phosphate levels when administered a high-phosphate diet and decreased urine phosphate levels following acute phosphate loading.
CONCLUSIONS: Phosphate elevations induced FGF23 expression in skeletal muscle, independent of the absence or presence of CKD. Skeletal muscle-derived FGF23 reduced renal phosphate reabsorption.

DOI: https://doi.org/10.1681/ASN.0000000963
Expert Rev Neurother. 2026 Jan 21.

Advancing treatment of spinal muscular atrophy through inhibition of the myostatin signaling pathway.

Richard S Finkel, Thomas O Crawford, Basil T Darras, Thomas Brown, Mouhamed Gueye, Mary Schroth, Jena M Krueger, Laurent Servais.

   INTRODUCTION: In spinal muscular atrophy (SMA), irreversible loss of spinal motor neurons and progressive skeletal muscle atrophy cause continuous weakness and loss of motor function. Treatments that increase levels of survival motor neuron (SMN) protein in motor neurons have greatly improved prognoses for patients, but significant unmet needs remain. Myostatin is a protein secreted by skeletal muscle that acts as a negative regulator of muscle growth. Inhibition of the myostatin signaling pathway may improve motor function in SMA and other neuromuscular diseases.
AREAS COVERED: This article reviews the role of muscle in SMA and the potential for treatments that inhibit the myostatin signaling pathway in neuromuscular diseases. Preclinical and clinical trial data are discussed for these muscle-targeted treatments in development for SMA.
EXPERT OPINION: SMN-targeted disease-modifying treatments focus on motor neuron survival rather than muscle. Treated individuals nonetheless experience a range of persistent muscle weakness. Treatments that inhibit myostatin signaling represent a potential complementary pathway for direct muscle enhancement. In the evolving SMA treatment landscape, understanding how muscle-targeted treatment can be incorporated into clinical practice will facilitate individualized treatment decisions and identify outcomes that best encapsulate maintenance or improvement of motor function across the phenotypic spectrum of SMA.

Keywords:  Apitegromab; clinical trial; emugrobart; motor function; muscle atrophy; myostatin; neuromuscular; spinal muscular atrophy; taldefgrobep alfa

DOI:  https://doi.org/10.1080/14737175.2026.2621405
J Nutr. 2026 Jan 20. pii: S0022-3166(26)00016-7. [Epub ahead of print] 101367

Vitamin B12 supports skeletal muscle oxidative phosphorylation capacity in male mice.

Luisa F Castillo, Katarina E Heyden, Abigail R Williamson, Wenxia Ma, Olga V Malysheva, Nathaniel M Vacanti, Anna E Thalacker-Mercer, Martha S Field.

   BACKGROUND: Vitamin B12 is a cofactor in folate-mediated one-carbon metabolism (FOCM), which generates nucleotides (thymidylate (dTMP) and purines) and methionine. Depressed de novo thymidylate (dTMP) synthesis leads to uracil accumulation in DNA.
OBJECTIVE: The purpose of this study was to determine how B12 availability affects mitochondrial DNA (mtDNA) integrity and mitochondrial function in skeletal muscle. B12 deficiency was modeled in young-adult mice. Intramuscular B12 injection in aged mice assessed the role of B12 supplementation in age-related changes in skeletal muscle.
METHODS: Male methionine synthase knockdown (Mtr+/-) and wild-type littermates (Mtr+/+) were weaned to either an AIN93G-based control (C) diet containing 25 μg/kg vitamin B12 (Mtr+/+, n=8; Mtr+/-, n=9) or a B12-deficient (-B12) diet containing 0 μg/kg vitamin B12 (n=9 per genotype) for seven weeks. Aged (20-22mo) male C57BL/6N mice were acclimated to an AIN93G control diet four weeks, then received either weekly injections of saline (vehicle control [30 uL 0.9% NaCl], n=5) or B12 (0.65 μg per 30uL 0.9% NaCl; n=6) in each of two hindleg muscles [1.25 μg B12 total]) for eight weeks. Outcomes measured included maximal oxygen consumption rate (OCR), uracil in mtDNA (a biomarker of mtDNA integrity), mtDNA copy number, and mitochondrial mass. Data were analyzed using a two-way ANOVA in the Mtr+/- mouse model exposed to B12-deficient diets and by a student's t-test for B12 supplementation in aged mice.
RESULTS: The tibialis anterior (TA) muscle from Mtr+/- mice exhibited 50% lower (p=0.01) maximal respiratory capacity of the electron transport chain than did TA from Mtr+/+ mice. Exposure to the -B12 diet lowered maximal capacity of complex I in mitochondrially rich muscle (soleus and mitochondria-rich portions of quadriceps and gastrocnemius) by 25% (p=0.02). Uracil in mitochondrial DNA (mtDNA) in red muscle and gastrocnemius was elevated ∼10 fold with exposure to -B12 diet (p=0.04 and p<0.001, respectively). In aged mice, gastrocnemius complex IV activity was increased 2-fold with intramuscular B12 supplementation (p=0.04).
CONCLUSIONS: Exposure to a B12-deficient diet led to uracil accumulation in mtDNA and impaired maximal oxidative capacity in skeletal muscle. B12 supplementation improved complex IV maximal capacity in gastrocnemius from aged mice, a model of age-related skeletal muscle decline.

Keywords:  Vitamin B12; mitochondrial DNA; oxidative phosphorylation; skeletal muscle; thymidylate; uracil

DOI:  https://doi.org/10.1016/j.tjnut.2026.101367
Diabetes. 2026 Jan 21. pii: db250625. [Epub ahead of print]

Integrating SMRT and Bulk RNA Sequencing With Metabolic Phenotyping to Examine Reduced Skeletal Muscle Mitochondrial Respiration in Type 2 Diabetes.

German Diabetes Study Group*

Recent advances in RNA sequencing (RNA-seq) techniques allow the identification of tissue-specific alternative splicing and can thereby provide new insights into molecular mechanisms of energy metabolism. Full-length transcriptomics based on single-molecule real-time sequencing (SMRT-seq) enable precise detection of isoforms with 99% accuracy in an unbiased manner. In this proof-of-concept study, we integrated SMRT-seq, bulk RNA-seq, and comprehensive metabolic phenotyping to investigate reduced mitochondrial function in the skeletal muscle of individuals with type 2 diabetes. Muscle biopsies were taken from nine individuals with type 2 diabetes and nine age- and BMI-matched glucose-tolerant men. Whole-body insulin sensitivity (WBIS) was assessed by hyperinsulinemic-euglycemic clamps, and muscle mitochondrial respiration was assessed by high-resolution respirometry. In muscle samples, SMRT-seq was used to create full-length reads and isoforms, which were mapped to the genome. Short-read sequencing was used to compare isoform expression between the groups. Participants with diabetes exhibited lower WBIS and fatty acid-driven and complex I-linked respiration compared with control participants. SMRT-seq revealed ∼67,000 isoforms originating from ∼14,000 unique genes. Although isoform numbers per gene did not differ, SMRT-seq-based mapping enabled refined data set clustering compared with conventional short-read sequencing and identified four splicing variants of the ATP5F1A gene encoding a subunit for ATP synthase. Among these, two novel transcripts were expressed exclusively in control participants. This study identified splicing variants of ATP synthase that were differentially expressed between participants with type 2 diabetes and those with normal glucose tolerance, which may contribute to the reduced fatty acid oxidation in diabetes.
ARTICLE HIGHLIGHTS: In our study, we developed a pipeline to integrate single-molecule real-time sequencing (SMRT-seq) with comprehensive metabolic phenotyping to examine reduced mitochondrial respiration in the skeletal muscle of individuals with type 2 diabetes. SMRT-seq revealed ∼67,000 isoforms originating from ∼14,000 unique genes; the isoform numbers per gene did not differ between participants with diabetes and matched control participants. Our data identified novel alternative splicing events, including two variants of the ATP5F1A gene encoding a subunit for ATP synthase. Among these, two novel transcripts were expressed exclusively in control participants. Our findings link transcriptomic changes to impaired mitochondrial respiration in type 2 diabetes, with the potential of providing novel therapeutic targets to improve metabolic health.

DOI: https://doi.org/10.2337/db25-0625
J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70183

Distinct Metabolomic Alterations Are Associated With Physical Function, Weight Loss, and Muscle Mass in Men With Cancer.

Lindsey J Anderson, Lu Xia, Haiming Kerr, Marin Cabrera, Fabien Chu, Jaqueline Rose, Peter C Wu, Atreya Dash, Sina A Gharib, Jose M Garcia.

   BACKGROUND: Treatments for cancer cachexia, defined as involuntary weight and muscle mass loss leading to significant functional impairment, remain unavailable partly due to insufficient improvement of clinically meaningful outcomes in current trials. By reflecting downstream effects of cellular function, metabolomics may identify mechanisms contributing to poor functional performance. Previous metabolomic studies in cancer cachexia have identified alterations in amino acid metabolism with weight loss or low muscularity; none have examined perturbations with poor physical function. We hypothesized that distinct metabolic signals in plasma and muscle are associated with weight loss, low muscle mass, and impaired function in cancer cachexia.
METHODS: We enrolled patients planning elective laparotomy for gastrointestinal or genitourinary cancer. Handgrip strength (HGS), stair climb power (SCP), and fasting plasma were collected within 2 weeks prior to surgery; rectus abdominis samples were obtained during surgery. Metabolomic perturbations associated with physical function (HGS, SCP), muscularity (lumbar cross-sectional area 'CSA' from opportunistic CT), or weight loss (> 5% over previous 6 months) were examined in plasma and muscle. The Mann-Whitney U-test compared metabolite abundance between weight-losing and weight-stable patients, while Spearman's correlation tested associations of abundance with CSA, HGS, or SCP. The 'Globaltest' method assessed pathway alterations with weight loss, CSA, HGS, or SCP; the Benjamini-Hochberg adjustment was used to control for false discovery.
RESULTS: Patients (N = 72) were male, median age 65 [interquartile range: 59-70], with 57% genitourinary cancer. Plasma and skeletal muscle metabolomic data were collected (N = 64 and N = 68, respectively). Weight loss was associated with significantly altered microbial, amino acid/derivative, fatty acid/lipid, and caffeine-related metabolism pathways in plasma (adjusted p < 0.1). Lower CSA was associated with significantly altered fatty acid/lipid, galactose, glycerophospholipid, and histidine metabolism and bile secretion pathways in skeletal muscle (adjusted p < 0.1). Worse HGS was nominally associated with altered plasma branched chain amino acid biosynthesis and altered skeletal muscle glutathione metabolism (unadjusted p ≤ 0.05), while worse SCP was nominally associated with altered skeletal muscle amino sugar/nucleotide sugar metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis (unadjusted p ≤ 0.05).
CONCLUSIONS: Significant metabolomic alterations in plasma and skeletal muscle characterized cancer-related weight loss and reduced CSA, respectively. Nominal, function-specific alterations were detected with worse HGS and SCP, which were distinct from those associated with weight loss or low CSA. Future larger studies may further characterize metabolomic profiles related to various functional outcomes and guide development of therapeutic targets to improve functional performance.

Keywords:  cancer cachexia; functional impairment; handgrip; metabolomics; skeletal muscle; stair climb

DOI:  https://doi.org/10.1002/jcsm.70183
Front Aging. 2025 ;6 1696473

Dietary polyphenols and sarcopenia: epigenetic mechanisms and geroscience perspectives for muscle health in aging.

Guilherme Da Silva Rodrigues, Leonardo Santos Lopes da Silva, Andressa Crystine da Silva Sobrinho, Jonas Benjamim, Gabriela Ferreira Abud, Gabriela Ueta Ortiz, Ellen Cristini de Freitas, Carlos Roberto Bueno Júnior.

  This review explores the effects of dietary polyphenols, such as resveratrol, quercetin, epigallocatechin gallate, and curcumin, on sarcopenia, with a particular focus on the underlying molecular and epigenetic mechanisms. These bioactive compounds may modulate key signaling pathways, including mTOR, NF-κB, and AMPK, while also influencing epigenetic processes such as DNA methylation, histone modifications, and microRNA regulation. Through these actions, polyphenols may reduce oxidative stress and chronic low-grade inflammation (inflammaging), enhance mitochondrial function, and contribute to the preservation of muscle mass and strength in older adults. Evidence from experimental and clinical studies investigating the impact of polyphenols on muscle health and their potential in the prevention or attenuation of sarcopenia will be discussed. In addition, current challenges and future perspectives will be addressed, emphasizing the role of epigenetic biomarkers and the potential synergy with physical exercise as part of integrated geroscience strategies to optimize muscle health during aging.

Keywords:  epigenetics; muscle aging; nutrigenomics; polyphenols; sarcopenia

DOI:  https://doi.org/10.3389/fragi.2025.1696473
Muscles. 2026 Jan 04. pii: 3. [Epub ahead of print]5(1):

The Myokine FGF-21 Responds in a Time-Dependent Manner to Three Different Types of Acute Exercise.

Mikal Thrones, Thomas Rawliuk, Dean M Cordingley, Stephen M Cornish.

  Background: The myokine response to various types of exercise may differ and influence the adaptations to various physiological systems in response to training. This study aimed to compare systemic myokines' (apelin, interleukin-6 [IL-6], interleu-kin-15 [IL-15], fibroblast-growth factor-21 [FGF-21], and irisin) responses to acute moderate-intensity cardiovascular exercise (MICE), high-intensity interval exercise (HIIE), or resistance exercise (RE). Methods: Six healthy, recreationally active adults (n = 4 males, n = 2 females) completed this crossover pilot study. After baseline testing, in a balanced randomized order, participants completed all three exercise sessions with one week between each of the exercise sessions. Blood samples were obtained at rest, immediately post-exercise, and 1 and 3 h post-exercise. Myokine response was analyzed using a 3 (exercise condition: MICE, HIIE, RE) × 4 (time: baseline, post-exercise, 1 and 3 h post-exercise) repeated-measures ANOVA. Results: Our results showed no significant interaction of time × exercise type in any of the analyzed myokines (all p > 0.05). A significant main effect of time was found for FGF-21, where concentrations at baseline (188.96 ± 127.34 pg/mL; p = 0.038) and immediately post-exercise (206.27 ± 135.95 pg/mL; p = 0.006) were higher than 3 h post-exercise (111.08 ± 127.65 pg/mL). No other main effects for time or exercise type were identified (all p > 0.05). Conclusions: The three exercise types, when analyzed together in this study, demonstrated a reduction in FGF-21 3 h post-exercise, suggesting this myokine was removed from the systemic circulation following exercise. The negative results of this study are inconclusive given the lower statistical power observed in this research. These preliminary results indicate the need for a larger trial to evaluate the effects of different types of exercise on the specificity of myokine responses and how acute exercise responses may translate into long-term exercise training adaptations.

Keywords:  FGF-21; IL-15; IL-6; apelin; cytokine; high-intensity exercise; irisin; moderate-intensity exercise; myokine; resistance exercise; skeletal muscle

DOI:  https://doi.org/10.3390/muscles5010003
Geroscience. 2026 Jan 19.

Age and sex shape plasma lipid associations to skeletal muscle mitochondrial respiration and H2O2 emission.

Nicholas A Carlini, Bradley A Ruple, Helya Rostamkhani, Huihui Shi, J Alan Maschek, Brady E Hanson, Namakkal Soorappan Rajasekaran, Russell S Richardson, Micah J Drummond, Ryan M Broxterman, Joel D Trinity.

  Aging changes the lipidome and mitochondrial function in a sex-dependent manner, yet their associations remain poorly understood. Twenty-four younger (7M/17F) and forty-three older (21M/22F) adults underwent blood draws and skeletal muscle biopsies for this cross-sectional investigation. Plasma lipidomic profiling was performed via liquid chromatography-tandem mass spectrometry, while peak mitochondrial O2 utilization (OXPHOS) and hydrogen peroxide (H2O2) emission were assessed using high-resolution respirometry. Plasma lipidomic analysis annotated 535 lipid species across 28 different lipid classes. Lipid-age associations were identified in four lipid classes for both sexes with twelve lipid classes demonstrating sex-specific associations, including triglycerides (TG), carnitines (CAR), and fatty acids (FA). For lipid-OXPHOS interactions, the primary lipid class and species associated with higher OXPHOS exclusively in males were ceramides (CER) and dimethyl cholesterol esters (dimethyl-CE), while TG were the primary lipid species associated with impaired OXPHOS in females. For lipid-H2O2 interactions, the primary lipid class and species associated with higher H2O2 were methyl desmosteryl esters (methyl-DE), methyl cholesterol esters (methyl-CE), FA and TG in males whereas females exhibited 10 (CE, SM, LPC, dihexosylceramides (Hex2Cer), LPE, PI, HexCer, LPI, CAR, and hexosyl-N-acetylneuraminyl-ceramides (Hex2NeuAcCer)) lipid classes associated exclusively with H2O2 emission. These findings establish novel age- and sex-specific relationships between age-related changes in plasma lipids and skeletal muscle mitochondrial function, revealing distinct lipid signatures for respiration and H2O2 emission in males and females.

Keywords:  Aging; Biological sex; Lipids; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.1007/s11357-025-02047-0
Front Cell Infect Microbiol. 2025 ;15 1710582

A review of omics studies in sarcopenia: from molecular mechanisms to hepatic-gut-muscle interactions in chronic liver disease comorbidity.

Xiaohui Xue, Jun Xu, Huijuan Wang, Kainan Wang, Yumu Chen, Yiting Xu, Shuping Que, Zhengtao Liu.

  Sarcopenia is an aging-related skeletal-muscle disorder characterized by progressive loss of muscle mass, strength, and function, and it frequently co-occurs with chronic liver disease (CLD) and other comorbidities. Conventional approaches struggle to resolve its pronounced heterogeneity, whereas multi-omics technologies now offer a systematic, molecular-level avenue to dissect its pathogenesis. By integrating ten omics studies of sarcopenia and six of CLD-associated sarcopenia, we propose a dual-layer "commonality-specificity" framework. At the level of commonality, we identify four core pathological pillars: proteostasis imbalance, mitochondrial dysfunction, chronic inflammation, and dysregulation of the gut-muscle axis. At the specificity level, focusing on the CLD context, we observe that these networks are selectively perturbed within the liver-disease microenvironment, leading us to advance the "cooperative accumulation of multiple weak signals" hypothesis to explain how multi-axis crosstalk drives muscle wasting in this setting. To date, omics findings remain largely correlational, posing challenges for clinical translation. Future investigations should integrate cutting-edge technologies-such as single-cell multi-omics, spatial transcriptomics, and computational modeling-to shift the research paradigm from static profiling to dynamic mechanistic dissection and precision intervention. This review provides both a theoretical foundation and a developmental roadmap for comprehensively understanding the mechanisms underlying sarcopenia comorbidities and for achieving precision diagnosis and treatment.

Keywords:  aging; chronic liver disease; gastrointestinal flora imbalance; gut-muscle axis; muscle-liver axis; omics analysis; sarcopenia

DOI:  https://doi.org/10.3389/fcimb.2025.1710582