bims-moremu 2025-09-21 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–09–21
35 papers selected by
Anna Vainshtein, Craft Science Inc.

Pancreatic Cancer Induces Population-Specific Switching of Myosin Isoforms and Discrete Activation of Cachexia Genes in Skeletal Muscle Myocytes.
Dual roles of mTOR in skeletal muscle adaptation: coordinating hypertrophic and mitochondrial biogenesis pathways for exercise-induced chronic disease management.
STX4 is indispensable for mitochondrial homeostasis in skeletal muscle.
Chondrolectin regulates the sublaminar localization and regenerative function of muscle satellite cells in mice.
Satellite Cell Ablation Limits Myofiber Regeneration but Not Angiogenesis Following Skeletal Muscle Injury.
Nicotinamide phosphoribosyltransferase (Nampt) in Lateral Hypothalamus Maintains Skeletal Muscle Functions Through Lactate-Mediated Calcium Signalling in Male Mice.
DYRK1A Overexpression Drives Muscle Wasting by Impeding Myogenesis via a USP7-Axin1-β-Catenin Regulatory Axis in Mice.
Simultaneous RNA Fluorescent In Situ Hybridization and Immunofluorescent Staining of Mouse Muscle Stem Cells on Fresh Frozen Skeletal Muscle Sections.
Lymphatic dysfunction is linked to disease pathogenesis in Duchenne muscular dystrophy animal models.
Lactate as an Exercise Mimetic: Mitigating Disuse Atrophy and Improving Muscle Endurance in Aging SAMP8 Mice.
Maximal-effort knee-extension exercise impairs skeletal muscle oxidative capacity and VO2 recovery in vivo.
Matrix metalloproteinases are hallmark early biomarkers and therapeutic targets in FSHD.
Intramuscular adipose tissue: from progenitor to pathology.
Phosphate and acidosis cause fiber-type specific changes to cellular and molecular contractile mechanics at 37°C in skeletal muscle from older adults.
Preterm Birth Conditions Alter Muscle Stem Cells and Their Niche, Causing Lasting Impairments in Muscle Regeneration and Function.
Arachidonic Acid Protects Skeletal Muscle Against Hyperglycaemia-Induced Muscle Atrophy by Modulating Myogenesis and Regulating KLF15 Expression in C57Bl/6 Mice.
Myokine-mediated muscle-organ interactions: Molecular mechanisms and clinical significance.
Unilateral isometric contraction induces REDD1 and suppresses insulin-stimulated mTORC1 and protein synthesis in non-contracted muscle of male mice.
Stem/progenitor cell-based therapy for Duchenne muscular dystrophy.
Mechanical Stimulation Induces Yap Mediated OCTN2 Transcription to Enhance Carnitine Metabolism in Sarcopenia.
The muscle specific MEF2Dα2 isoform promotes muscle ketolysis and running capacity in mice.
Embedding muscle fibers in hydrogel improves viability and preserves contractile function during prolonged ex vivo culture.
Radiation-induced impairment of skeletal muscle regeneration.
P2X7 Receptor acts as a novel target for ameliorating Sepsis-induced skeletal muscle atrophy in mice model.
Atrazine exposure induces skeletal muscle atrophy: Multi-omics insights into mechanisms and therapeutic targets.
Differentially expressed fusogens specify myocyte states to drive myogenesis.
High-Calorie Diet During Pregnancy Leads to Muscular Fibrosis and Neuromuscular Damage in Offspring Mice.
Quantification of Exercise-Induced Sarcomeric Damage in R349P Desmin Knock-In Mice: A New Approach in Myofibrillar Myopathy Research.
Nanoparticle delivery of AMPK activator 991 prevents its toxicity and improves muscle homeostasis in Duchenne muscular dystrophy.
Latest Updates on Sarcopenia and Cachexia: Insights from the 17th Sarcopenia, Cachexia, and Wasting Disorders Conference.
Baculovirus-mediated gene transfer enables functional expression of the PIEZO1 ion channel in isolated muscle satellite cells.
Roles of plasminogen activator inhibitor-1 in aging-related muscle and bone loss in mice.
Exercise-Induced Epigenetic Modifications: Implications for Healthy Aging.
Transcriptome and microRNAome profiling of human skeletal muscle in pancreatic cancer cachexia.
A novel mouse model for LAMA2-related muscular dystrophy with analysis of molecular pathogenesis and clinical phenotype.

bioRxiv. 2025 Sep 05. pii: 2025.09.01.673500. [Epub ahead of print]

Pancreatic Cancer Induces Population-Specific Switching of Myosin Isoforms and Discrete Activation of Cachexia Genes in Skeletal Muscle Myocytes.

Brittany R Counts, Sephora Jean, Omnia Gaafer, Sara K Ota, Iishaan Inabathini, Tingbo Guo, Denis C Guttridge, Michael C Ostrowski, Leonidas G Koniaris, Sha Cao, Hyun C Roh, Teresa A Zimmers.

Skeletal muscle loss in pancreatic cancer is a significant cause of morbidity and mortality for patients. In order to understand myocytes changes we examined myonuclei- and myofiber-specific dynamics during pancreatic cancer cachexia progression. Single-nucleus RNA-seq was used to interrogate myonuclear gene expression, and RNAscope and immunofluorescence characterized myofiber-specific changes. Bulk RNA-seq of skeletal muscle provided a whole-muscle transcriptomic profile. Cachexia induces a progressive loss of muscle differentiation factor Maf and its target Myh4 , accompanied by increased expression of Myh1 and Myh2 . This myofiber dedifferentiation occurs without evidence for fiber type shifting, regeneration, or proliferation. Single-nuclei analysis reveals global shifts in myofiber gene expression identity including the identification of a cachexia only myonuclear subpopulation. Cachexia gene expression was not restricted solely to this PDAC-specific myonuclear subpopulation and did not overlap with Myh1 and Myh2 expressing myonuclei early in cachexia. Altogether, PDAC cachexia elicits distinct transcriptional responses across different myonuclear populations. These results reveal population-specific heterogeneity in cachexia gene activation, rather than a uniform upregulation of cachexia mediators across muscle tissue. Our data suggest that myonuclei fate occurs prior to overt muscle wasting when cachexia gene expression only modestly overlaps with differentiation factors, with a strong association after irreversible muscle wasting. These findings explain the challenge of effectively targeting skeletal muscle wasting in cancer cachexia requires addressing the changing cell population induced through non overlapping mechanisms.

DOI: https://doi.org/10.1101/2025.09.01.673500
Front Med (Lausanne). 2025 ;12 1635219

Dual roles of mTOR in skeletal muscle adaptation: coordinating hypertrophic and mitochondrial biogenesis pathways for exercise-induced chronic disease management.

Yong-Cai Zhao.



Keywords:  exercise; hypertrophy; mammalian target of rapamycin (mTOR); mitochondrial biogenesis; skeletal muscle

DOI:  https://doi.org/10.3389/fmed.2025.1635219
bioRxiv. 2025 Sep 03. pii: 2025.09.02.673840. [Epub ahead of print]

STX4 is indispensable for mitochondrial homeostasis in skeletal muscle.

Joseph M Hoolachan, Rekha Balakrishnan, Erika M McCown, Karla E Merz, Chunxue Zhou, Elizabeth Bloom-Saldana, Patrick T Fueger, Angelica Hamilton, Tali Kiperman, Ke Ma, Eunjin Oh, Lei Jiang, Patrick Pirrotte, Orian Shirihai, Debbie C Thurmond.

Background: Mitochondrial homeostasis is vital for optimal skeletal muscle integrity. Mitochondrial quality control (MQC) mechanisms that are essential for maintaining proper functions of mitochondria include mitochondrial biogenesis, dynamics and mitophagy. Previously, Syntaxin 4 (STX4) traditionally considered a cell surface protein known for glucose uptake in skeletal muscle, was also identified at the outer mitochondrial membrane. STX4 enrichment was sufficient to reverse Type 2 diabetes-associated mitochondrial damage in skeletal muscle by inactivation of mitochondrial fission. However, whether STX4 could modulate skeletal muscle mitochondrial homeostasis through MQC mechanisms involving mitochondrial biogenesis or mitophagy remains to be determined.
Methods: To determine the requirements of STX4 in mitochondrial structure, function and MQC processes of biogenesis and mitophagy, we implemented our in-house generated inducible skeletal muscle-specific STX4-knockout (skmSTX4-iKO) mice ( Stx4 fl/fl ; Tg(HSA-rtTA/TRE-Cre )/B6) and STX4-depleted immortalized L6.GLUT4myc myotubes via siRNA knockdown (siSTX4).
Results: We found that non-obese skmSTX4-iKO male mice (>50% reduced STX4 abundance, Soleus and Gastrocnemius ***p<0.001, Tibialis anterior (TA) ****p<0.0001) developed insulin resistance (**p<0.01), together with reduced energy expenditure (AUC *p<0.05), respiratory exchange ratio (AUC **p<0.01), and grip strength (*p<0.05). STX4 ablation in muscle also impaired mitochondrial oxygen consumption rate (****p<0.0001). Mitochondrial morphological damage was heterogenous in STX4 depleted muscle, presenting with small fragmented mitochondria (****p<0.0001) and deceased electron transport chain (ETC) abundance (CI ***p<0.001, CII *p<0.05, CIV **p<0.01) in oxidative soleus muscle, while glycolytic TA fibers display enlarged swollen mitochondria (****p<0.0001) with no change in ETC abundance. Notably, >60% reduction of STX4 in siSTX4 L6.GLUT4myc myotubes (****p<0.0001) also decreased ETC abundance (CI ****p<0.0001, CII ****p<0.0001, CIV *p<0.05) without changes in mitochondrial glucose metabolism, as shown by [U- 13 C] glucose isotope tracing. For MQC, both skmSTX4-iKO male mice (*p<0.05) and siSTX4 L6.GLUT4myc myotubes (*p<0.05) showed decreased mitochondrial DNA levels alongside reduced mRNA expression of mitochondrial biogenesis genes Ppargc1a (PGC1-α, *p<0.05) and Tfam (*p<0.05) in skmSTX4-iKO soleus muscle and PGC1-α (mRNA *p<0.05, protein ***p<0.001), NRF1 (mRNA and protein *p<0.05) and Tfam (mRNA *p<0.05) in siSTX4 L6.GLUT4myc myotubes. Furthermore, live cell imaging using mt-Keima mitophagy biosensor in siSTX4 L6.GLUT4myc cells revealed significantly impaired mitochondrial turnover by mitophagy (*p<0.05) and mitochondria-lysosome colocalization (*p<0.05). STX4 depletion also reduced canonical mitophagy markers, PINK1 and PARKIN in both skmSTX4-iKO muscle (PARKIN *p<0.05, PINK1 **p<0.01) and siSTX4 L6.GLUT4myc myotubes (PARKIN ****p<0.0001, PINK1 *p<0.05).
Conclusions: Our study demonstrated STX4 as a key mitochondrial regulator required for mitochondrial homeostasis in skeletal muscle.

DOI: https://doi.org/10.1101/2025.09.02.673840
bioRxiv. 2025 Sep 13. pii: 2025.09.09.675211. [Epub ahead of print]

Chondrolectin regulates the sublaminar localization and regenerative function of muscle satellite cells in mice.

Lijie Gu, Kun Ho Kim, Xiyue Chen, Stephanie N Oprescu, Yufen Li, Junxiao Ren, Shihuan Kuang, Feng Yue.

Skeletal muscle satellite cells (SCs) reside between the myofiber sarcolemma and basal lamina, where extracellular matrix (ECM) interactions are essential for their maintenance and regenerative function. Here, we identify chondrolectin (CHODL), a type I transmembrane protein with a C-type lectin domain, as a critical regulator of SC biology. Single-cell RNA-seq analysis reveals that Chodl is highly enriched in quiescent SCs but downregulated in proliferating myoblasts. Using conditional knockout models, we show that deletion of Chodl in embryonic myoblasts (ChodlMKO) or adult SCs (ChodlPKO) does not affect muscle development but markedly impairs regeneration in both young and aged mice. Chodl-deficient SCs exhibit reduced self-renewal, diminish proliferation, and impair differentiation, leading to defective myofiber repair. In silico network perturbation further predicts disruption of ECM-ligand interactions and Notch signaling, consistent with our observation that a significant fraction of SCs in ChodlPKO mice localize outside the basal lamina and undergo precocious activation. Together, these findings establish CHODL as a key determinant of SC niche localization and regenerative function, uncovering a previously unrecognized mechanism linking ECM interactions to muscle stem cell maintenance and repair.

DOI: https://doi.org/10.1101/2025.09.09.675211
Microcirculation. 2025 Oct;32(7): e70024

Satellite Cell Ablation Limits Myofiber Regeneration but Not Angiogenesis Following Skeletal Muscle Injury.

Nicole L Jacobsen, Michael A Nguyen, Aaron B Morton, Ddw Cornelison, Steven S Segal.

   OBJECTIVE: Myotoxin injury of skeletal muscle disrupts myofibers and fragments capillaries. Following injury, myofibers and capillaries regenerate in concert; however, it remains unresolved whether myogenesis and angiogenesis are interdependent processes. We tested the hypothesis that myofiber regeneration is required for revascularization.
METHODS: To limit myofiber regeneration, satellite cells were depleted by tamoxifen injections (+TMX) in adult Pax7-CreERT2/+; RosaDTA/+ (Pax7-DTA) mice; vehicle injections (-TMX) served as controls. Two weeks later, the gluteus maximus muscle was injured by local injection of BaCl2. Regeneration of myofibers and microvessels was assessed histologically. Microvascular perfusion was evaluated with fluorescent tracers injected into the bloodstream.
RESULTS: Myofiber regeneration was minimal in +TMX. Through 21 days post injury (dpi), microvascular area (CD31 immunostaining) was similar between +TMX and -TMX, with disoriented microvessels prevailing in +TMX. At 7 dpi, fewer capillaries were perfused in +TMX compared to -TMX. At 21 dpi, EC area and capillary perfusion were not different between groups. For +TMX at 28 dpi, distinct regions with fewer perfused microvessels near "ghost" fibers were accompanied by adjacent areas of robust vascularity and clusters of adipocytes.
CONCLUSIONS: Following myotoxin injury after satellite cell ablation, angiogenesis ensues without myogenesis, and the microcirculation remodels according to changes in tissue composition.

Keywords:  Pax7; angiogenesis; myogenesis; regeneration; satellite cells; skeletal muscle

DOI:  https://doi.org/10.1111/micc.70024
J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70055

Nicotinamide phosphoribosyltransferase (Nampt) in Lateral Hypothalamus Maintains Skeletal Muscle Functions Through Lactate-Mediated Calcium Signalling in Male Mice.

Takahiro Eguchi, Keiko Kabetani, Naoki Ito.

   BACKGROUND: Sarcopenia has become an urgent socioeconomic problem in rapidly aging societies. The pathogenesis of age-associated sarcopenia is not fully understood and no effective therapeutic strategies have been developed to date. Recent studies have suggested the importance of the functional linkage between the brain and skeletal muscles in the pathogenesis of sarcopenia. However, the functional connections between the brain and skeletal muscles, particularly between the hypothalamus and skeletal muscles, remain unclear. In this study, we focused on the importance of nicotinamide adenine dinucleotide (NAD+) metabolism in the lateral hypothalamus (LH) and explored the importance of the NAD+-mediated functional connection between the LH and skeletal muscle and its involvement in the pathogenesis of sarcopenia.
METHODS: To explore the role of NAD+ in the LH, we knocked down nicotinamide phosphoribosyltransferase (Nampt), a rate-limiting enzyme in the NAD+ salvage pathway that is required for the maintenance of NAD+, by stereotaxic injection of a lentivirus encoding short hairpin RNA for Nampt into the LH.
RESULTS: Loss-of-function of Nampt in the LH caused decreased muscle mass (mg/cm) [tibialis anterior: 24.8 ± 0.36 vs. 22.9 ± 0.29, p < 0.001; gastrocnemius: 65.7 ± 1.60 vs. 60.9 ± 0.65, p < 0.05] and strength (mN) [382.0 ± 10.4 vs. 345.7 ± 5.47 at 100 Hz stimulation, p < 0.01], accompanied by disruption of the p70S6K-S6 protein synthesis axis in skeletal muscle. Skeletal muscle of LH-specific Nampt-knockdown mice exhibited decreased levels of pyruvate and lactate, the end products of glycolysis and decreased levels of glucose metabolism-related genes, such as β2 adrenergic receptor (β2-AR), peroxisome proliferator-activated receptor delta (PPARδ), PPARγ and pyruvate dehydrogenase kinase 4 (PDK4). We identified lactate as a mediator linking decreased glycolysis and protein synthesis. Lactate induces increases in intracellular Ca2+ levels, which induce the activation of the p70S6K-S6 protein synthesis axis.
CONCLUSIONS: Our results indicate that Nampt in the LH maintains skeletal muscle function by regulating lactate-mediated Ca2+ signalling in skeletal muscle. Our study highlights the essential role of Nampt in the LH in the regulation of skeletal muscles and lactate as a mediator that links glycolysis and protein synthesis. As NAD+ levels in the LH decrease with age, our study provides new insights into the pathogenesis of sarcopenia.

Keywords:  Ca2+ signalling; NAD+; Nampt; lactate; lateral hypothalamus; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.70055
IUBMB Life. 2025 Sep;77(9): e70061

DYRK1A Overexpression Drives Muscle Wasting by Impeding Myogenesis via a USP7-Axin1-β-Catenin Regulatory Axis in Mice.

Mei Lu, Xiaohui Li, Lin Ma, Xingbang Wang, Jun Ma, Juan Zhao, Qunshan Lu.

  Muscle wasting, characterized by loss of muscle mass and strength, severely impacts patient quality of life and is associated with numerous chronic diseases and aging. The molecular mechanisms are complex, involving protein synthesis/degradation imbalance. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) and ubiquitin-specific peptidase 7 (USP7) have diverse cellular roles, but their coordinated function in skeletal muscle homeostasis remains poorly understood. DYRK1A overexpression in vivo induced muscle atrophy phenotypes, including reduced muscle mass, grip strength, fiber cross-sectional area (CSA), altered fiber type composition, and neuromuscular junction integrity, accompanied by elevated atrophy markers: muscle atrophy F-box protein (Atrogin-1), muscle ring finger 1 (MuRF-1), myostatin and suppressed myogenic markers: myoblast determination protein 1 (MyoD), myogenin (MyoG), myocyte enhancer factor 2C (Mef2c), myogenic factor 5 (Myf5). Conversely, pharmacological inhibition of DYRK1A with Harmine ameliorated these atrophy phenotypes in transgenic DYRK1A overexpressing (TgD) mice. In vivo, USP7 deficiency resulted in similar muscle wasting phenotypes. In vitro, DYRK1A overexpression or USP7 overexpression inhibited C2C12 myoblast proliferation and differentiation, effects rescued by Wnt3a treatment or USP7 knockdown, respectively. Mechanistically, DYRK1A activity suppressed active β-catenin levels. USP7 was found to interact with and deubiquitinate axis inhibition protein 1 (Axin1), leading to its stabilization. Knockdown of USP7 increased Axin1 ubiquitination and degradation, thereby promoting β-catenin signaling and myogenesis, counteracting the effects of DYRK1A. Our findings reveal a novel signaling axis where DYRK1A and USP7 cooperatively suppress Wnt/β-catenin signaling to promote muscle wasting. DYRK1A likely acts upstream, potentially phosphorylating pathway components, whereas USP7 stabilizes the β-catenin destruction complex scaffold protein Axin1 through deubiquitination. This coordinated action inhibits myogenesis and activates atrophy pathways. Targeting DYRK1A or USP7 could represent promising therapeutic strategies for muscle wasting disorders.

Keywords:  Axin1; DYRK1A; USP7; Wnt/β‐cateninAxin1; muscle atrophy; myogenesis; sarcopenia; ubiquitination

DOI:  https://doi.org/10.1002/iub.70061
Bio Protoc. 2025 Sep 05. 15(17): e5435

Simultaneous RNA Fluorescent In Situ Hybridization and Immunofluorescent Staining of Mouse Muscle Stem Cells on Fresh Frozen Skeletal Muscle Sections.

Vedant R Lakkundi, Maria L Perez, Kartik Soni, Albert E Almada.

  Adult muscle stem cells (MuSCs) are the key cellular source for regenerating skeletal muscle in vertebrates. MuSCs are typically identified in skeletal muscle by the expression of the paired box protein 7 (PAX7) protein. Here, we developed a combined RNA fluorescent in situ hybridization (FISH) using RNAscope technology and an immunofluorescence (IF) protocol for the simultaneous detection of Pax7 mRNA and PAX7 protein in individual MuSCs in vivo. Interestingly, we show that while most PAX7+ (protein) MuSCs express Pax7 mRNA, there is a subset of Pax7 + (mRNA) cells that do not express PAX7 protein. Altogether, we developed a combined FISH/IF protocol that allows for the co-detection of mRNA and protein in MuSCs in vivo, a strategy that can be applied to any target gene. The functional significance of the Pax7-expressing subset of cells lacking PAX7 protein prior to injury remains unknown. Key features • Extensive step-by-step details for an optimized protocol combining traditional immunofluorescence with RNA fluorescent in situ hybridization (FISH) using ACDBio's RNAscope technology. • Allows for the co-detection of protein and mRNA in muscle stem cells (MuSCs) in mouse skeletal muscle tissue in vivo in ~2 days. • Validation of our protocol uncovers a subset of cells expressing Pax7 mRNA but not PAX7 protein.

Keywords:  Fluorescent in situ hybridization (FISH); Immunofluorescence (IF); Muscle stem cells; PAX7; RNAscope; Skeletal muscle

DOI:  https://doi.org/10.21769/BioProtoc.5435
Proc Natl Acad Sci U S A. 2025 Sep 23. 122(38): e2505656122

Lymphatic dysfunction is linked to disease pathogenesis in Duchenne muscular dystrophy animal models.

Bhuvaneshwaran Subramanian, Shedreanna Johnson, Akshaya Narayanan, Wei Wang, Bonnie L Seaberg, Jillian Ball, Ilse M Paredes Mares, Ahana Majumder, Alexandria Aceves, Sarah E Frazier, Alexis Rutledge, John F Griffin, Soumiya Pal, Scott Zawieja, Michael J Davis, Joseph M Rutkowski, Peter P Nghiem, Mendell Rimer, Mariappan Muthuchamy.

  Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder characterized by progressive muscle weakness and inflammation caused by mutations in the DMD gene. Chronic inflammation in DMD exacerbates the complications associated with disease progression. Since the lymphatic system plays a crucial role in regulating and resolving inflammation, our primary goal was to investigate whether lymphatics were dysregulated in skeletal muscle of DMD animals. We used the D2.mdx murine and golden retriever muscular dystrophy (GRMD) canine models, as well as mouse and rat lymphatic muscle cells (LMCs) to determine the role of dystrophin in lymphatic structure and function in skeletal muscles. Single-cell RNA sequencing data from control LMCs showed dystrophin expression, and protein results demonstrated that the 427-, 140-, and 71-kDa dystrophin isoforms were detectable in the LMCs from control mice, whereas the 427 kDa isoform was undetectable in LMCs derived from D2.mdx mice. Microlymphangiography and magnetic resonance lymphangiogram results showed a significant decrease in lymph transport in D2.mdx mice and GRMD dogs, respectively. Isolated flank lymphatic vessels from D2.mdx mice exhibited an increase in tonic contraction and a significant decrease in the phasic contractile frequency and amplitude, supporting lymphatic vessel dysfunction. The gene expression profile and immunofluorescence analyses of dystrophic muscle revealed inflammatory lymphangiogenesis in dystrophic muscle. Skeletal muscle tissues that showed improvement in function after adeno-associated virus-microdystrophin treatment also showed significant improvement in inflammatory lymphangiogenesis in GRMD dogs. Thus, these results show a linkage between lymphatic function and DMD pathogenesis that merits further investigation in DMD patients.

Keywords:  Duchenne muscular dystrophy; inflammation; lymph transport; lymphatic muscle; lymphatic vessel function

DOI:  https://doi.org/10.1073/pnas.2505656122
Mol Cell Biol. 2025 Sep 17. 1-19

Lactate as an Exercise Mimetic: Mitigating Disuse Atrophy and Improving Muscle Endurance in Aging SAMP8 Mice.

Zhen Qi, Xi Liu, Yifen Chen, Linglin Zhang, Longhe Yang, Caihua Huang, Donghai Lin.

  Lactate, historically considered a metabolic byproduct, has emerged as a key regulator of muscle physiology and metabolism. This study explores its potential as an exercise mimetic to counteract disuse muscle atrophy (DMA) in aging skeletal muscle using a hindlimb suspension model in senescence-accelerated prone 8 (SAMP8) mice. The mice were divided into four groups: Control, lactate-treated control, hindlimb suspension, and hindlimb suspension with lactate intervention. Lactate administration preserved gastrocnemius muscle mass, restored muscle strength, and attenuated oxidative fiber atrophy. Electrophoretic and histological analyses showed increased MyHC I expression, indicating protection of oxidative fibers. Functional assessments revealed improved muscle endurance and contractile force, while metabolomic profiling identified changes in energy metabolism, amino acid metabolism, and protein synthesis pathways. Specifically, lactate improved impaired branched-chain amino acid metabolism, suggesting enhanced protein synthesis. In addition, lactate boosted Cori cycle activity, upregulated hepatic lactate transporters, and increased lactate dehydrogenase B activity, facilitating efficient lactate metabolism and gluconeogenesis. These results provide new insights into the role of lactate as a metabolic regulator and highlight its potential as a therapeutic intervention to combat exercise-induced muscle wasting and preserve muscle function in aging and immobilized individuals.

Keywords:  Lactate; NMR-based metabolomics; aging skeletal muscle; disuse muscle atrophy; exercise mimetic

DOI:  https://doi.org/10.1080/10985549.2025.2551616
J Appl Physiol (1985). 2025 Sep 18.

Maximal-effort knee-extension exercise impairs skeletal muscle oxidative capacity and VO2 recovery in vivo.

Miles F Bartlett, Andrew P Oneglia, Delaney Davis, Sauyeh Zamani, Ashfaq Siddiqui, Mark D Ricard, Michael D Nelson.

  In the present study, we examined how fatiguing exercise affects O2-based measures of skeletal muscle oxidative capacity in vivo by measuring changes in the rate constant of muscle VO2 recovery (kVO2). Healthy young adults completed isokinetic (120º∙s-1), maximal voluntary dynamic contractions (MVDCs) lasting 24- (baseline kVO2) and 240 s (post-fatiguing exercise kVO2). Vastus lateralis kVO2 was measured using near-infrared diffuse correlation spectroscopy (NIRS-DCS) via the conventional repeated arterial occlusion method (Part-A, n=14) or a novel NIRS-DCS 'free-flow' method (Part-B, n=13). Pulmonary VO2 (pVO2), muscle VO2 (mVO2), and surface electromyography (sEMG) measures of muscle activation were also measured throughout the 240-s trial. Compared to the 24-s trial, kVO2 following 240s of MVDCs was impaired by ~25% (Part-A; p=0.005) and ~16% (Part-B; p=0.017). Moreover, both pVO2 and mVO2 rapidly increased to maximal levels, where they remained for the duration of the 240-s trial, despite sEMG activity and peak MVDC power declining. These results demonstrate that fatiguing exercise not only impairs O2-based measures of skeletal muscle oxidative capacity, but that mitochondrial O2-consumption is uncoupled from power output and ATP demand during fatiguing exercise.

Keywords:  NIRS-DCS; VO2 slow component; mitochondria; oxidative capacity; skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00517.2025
JCI Insight. 2025 Sep 18. pii: e195104. [Epub ahead of print]

Matrix metalloproteinases are hallmark early biomarkers and therapeutic targets in FSHD.

Usuk Jung, Erdong Wei, Haseeb Ahsan, Ana Mitanoska, Kenric Chen, Michael Kyba, Darko Bosnakovski.

  Matrix remodeling by metalloproteinases (MMPs) is essential for maintaining muscle homeostasis; however, their dysregulation can drive degenerative processes. By interrogating biopsy RNA-seq data, we show that MMP expression correlates with disease severity in facioscapulohumeral muscular dystrophy (FSHD). In the iDUX4pA FSHD mouse model, MMP levels also progressively increase in response to DUX4-induced muscle degeneration. Single-cell RNA-seq further identifies fibroadipogenic progenitors (FAPs) and macrophages as the primary sources of MMPs, particularly MMP2, MMP14, and MMP19, in dystrophic muscle. Treatment with the pan-MMP inhibitor Batimastat alleviates inflammation and fibrosis, improves muscle structure, and decreases the number of FAPs and infiltrating macrophages. These findings underscore the role of MMPs in driving muscle degeneration in FSHD, highlight MMPs as functional biomarkers of disease, and support MMP inhibitors as a DUX4-independent therapeutic approach to limit fibroadipogenesis and promote muscle regeneration.

Keywords:  Cell biology; Fibrosis; Muscle biology

DOI:  https://doi.org/10.1172/jci.insight.195104
Am J Physiol Cell Physiol. 2025 Sep 15.

Intramuscular adipose tissue: from progenitor to pathology.

Hailey G Jones, Daniel Kopinke, Gretchen A Meyer.

  The accumulation of intramuscular adipose tissue (IMAT) is a nearly ubiquitous feature of skeletal muscle pathology, strongly correlating with impaired contractility and metabolic dysfunction across a wide spectrum of clinical conditions, from aging and obesity to genetic myopathies and orthopaedic injuries. For decades, a critical question has persisted: is IMAT a passive biomarker of disease progression or an active pathogenic agent? This review synthesizes emerging evidence to address this question by exploring several key areas. We first evaluate the mechanisms by which IMAT impairs muscle function, examining evidence for its dual role as both a physical disruptor and a local source of unbalanced paracrine signals. By integrating findings from human studies with insights from diverse animal models, we also highlight significant translational challenges, particularly the resistance of common rodent models to developing human-like IMAT pathology. Furthermore, we review the cellular origin of IMAT to resident fibro/adipogenic progenitors (FAPs), a highly plastic cell population that supports regeneration in healthy muscle but can differentiate into adipocytes under pathological conditions. We then dissect the complex signaling network that governs this fate switch-specifically the balance between pro-adipogenic 'triggers' and inhibitory 'brakes' that becomes dysregulated in disease. The evidence increasingly points to IMAT as an active contributor to muscle decline. Therefore, future progress requires a multi-pronged approach: the continued elucidation of the specific molecular 'brakes' and 'triggers' that govern FAP fate, the development of more translationally relevant preclinical models, and the standardization of IMAT quantification methods to improve diagnostic accuracy and clinical trial endpoints.

Keywords:  Fatty infiltration; IMAT; Intermuscular adipose tissue; Muscle degeneration; Muscle pathology

DOI:  https://doi.org/10.1152/ajpcell.00613.2025
bioRxiv. 2025 Sep 03. pii: 2025.08.28.672942. [Epub ahead of print]

Phosphate and acidosis cause fiber-type specific changes to cellular and molecular contractile mechanics at 37°C in skeletal muscle from older adults.

Brent A Momb, Jane A Kent, Stuart R Chipkin, Mark S Miller.

Intracellular accumulation of hydrogen ions (H + ) and inorganic phosphate (P i ) have temperature-dependent effects on single fiber contractile function between 10-30°C. In vivo , human skeletal muscle temperatures range between 35-38°C, and although contractile function is highly dependent on temperature, the effects of fatigue-inducing [H + ] and [P i ] on contractile mechanics at 37°C is unknown. Using sinusoidal analysis, the independent and combined effects of these metabolites on cellular and molecular contractile function were determined at 37°C in slow-contracting myosin heavy chain (MHC) I and fast-contracting MHC IIA fibers from vastus lateralis muscle of 13 older adults (8 females), under four conditions: maximal calcium activation ("control"; 5 mM P i , pH 7.0), high P i (30 mM), low pH (6.2), and fatigue (30 mM P i and pH 6.2). Specific tension (force/cross-sectional area, mN/mm 2 ) in both fiber types was reduced only under fatigue conditions (20-26%). MHC I fibers had slower cross-bridge kinetics with fewer or less stiff strongly-bound myosin-actin cross-bridges in high P i , low pH, and fatigue. In contrast, fatigued MHC IIA fibers had faster cross-bridge kinetics with increased myofilament and/or cross-bridge viscosity. Single fiber oscillatory work was reduced in both fiber types when P i or pH alone was altered. However, fatigue conditions returned oscillatory work values toward control through alterations to cross-bridge kinetics in MHC I fibers and changes to work absorption and production processes in MHC IIA fibers. These findings quantify fiber-type specific mechanical and kinetic mechanisms of fatigue in human skeletal muscle at 37°C, thus advancing our understanding of metabolite-based muscle fatigue in vivo .
KEY POINTS SUMMARY: Working skeletal muscle increases intracellular concentrations of hydrogen ion and inorganic phosphate, leading to fatigue, or loss of force-generating capacityTemperature plays a well-established role in the muscle response to hydrogen ion and/or inorganic phosphate accumulation, but has not previously been studied at human body temperature (37°C)At 37°C, reduced force generation only occurs when high phosphate and hydrogen ions are combined, not when changed individuallyIn slow-contracting fibers, fatigue slowed myosin-actin cross-bridge kinetics and reduced the number or stiffness of strongly-bound cross-bridges. In fast-contracting fibers, fatigue increased myosin-actin cross-bridge kinetics and increased myofilament viscosity.The distinct responses by fiber type to fatigue provides new insight into its mechanisms and advances our understanding of the whole muscle and body responses to fatigue.
Abstract Figure:

DOI: https://doi.org/10.1101/2025.08.28.672942
J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70058

Preterm Birth Conditions Alter Muscle Stem Cells and Their Niche, Causing Lasting Impairments in Muscle Regeneration and Function.

Alyson Deprez, Thomas Molina, Gael Cagnone, Pauline Garcia, Séverine Leclerc, Anik Cloutier, Rebecca Desaulniers, Benjamin Ellezam, Anne Monique Nuyt, Nicolas A Dumont.

   BACKGROUND: Preterm birth-related conditions affect the development of multiple organs, such as the heart, the lungs and the brain, leading to long-term alterations in their function and a higher risk of comorbidities. Emerging evidence also indicates that the skeletal muscles are affected. We aimed to understand the mechanisms underlying these changes in skeletal muscles.
METHODS: A rodent model of transient neonatal hyperoxia and muscle samples of human babies born at term or preterm were used to investigate the impact of preterm birth-related conditions on muscle stem cells, the engine of muscle growth and repair. Single cell transcriptomics, in vitro culture of myoblasts or single myofibres, ex vivo muscle contractile properties and in vivo experiments (cardiotoxin-induced muscle injury) were performed to determine the impact of preterm birth on muscle stem cell function and regenerative capacity.
RESULTS: Preterm birth-related conditions reduced the muscle stem cell pool from the newborn stage (-30%, p = 0.0134) until adulthood (-56%, p < 0.0001), along with impaired myogenic capacity and regenerative potential. In vitro analysis from rats showed impaired self-renewal and reduced myotube size (-28.8%, p = 0.004). Human samples suggest a similar trend towards smaller myotube size in muscle stem cells from infants born at the earlier gestational age. Single-cell RNA-seq on rat samples revealed an enriched TNF-α/NF-κB signalling pathway within subsets of muscle stem cells. This pathway, mediated in part by interaction with macrophages, influences muscle stem cell fate decisions and myogenic trajectories. Culture experiments showed that myotubes treated with conditioned medium from macrophages of rats exposed to hyperoxia have reduced diameters (-66.5%, p = 0.0216). Early administration of an inhibitor of TNF-α (Infliximab) restored the muscle stem cell pool postinjury (63%, p = 0.0073) and regenerative capacity.
CONCLUSIONS: Overall, preterm birth-related conditions promote an inflammatory microenvironment that disrupts the muscle stem cell pool and their function. This mechanism could explain the muscle atrophy and weakness observed in individuals born preterm and suggests potential therapeutic strategies to improve overall health outcomes in this population.

Keywords:  inflammation; muscle stem cells; myogenesis; preterm birth; regeneration

DOI:  https://doi.org/10.1002/jcsm.70058
FASEB J. 2025 Sep 30. 39(18): e71036

Arachidonic Acid Protects Skeletal Muscle Against Hyperglycaemia-Induced Muscle Atrophy by Modulating Myogenesis and Regulating KLF15 Expression in C57Bl/6 Mice.

Akash Mitra, Debajit Chaudhury, Akhila Balakrishna Rai, Undurti N Das, Thottethodi Subrahmanya Keshava Prasad, Bipasha Bose, Sudheer Shenoy P.

  Glucotoxicity or hyperglycemia as a consequence of Type 1 diabetes affects numerous tissues, including skeletal muscles, and translates to muscle wasting or atrophy. Since 40% of the total body weight comprises skeletal muscles, and because this tissue plays an essential role in voluntary movement, protecting its integrity is crucial for maintaining whole-body homeostasis. Although different studies have investigated the role of arachidonic acid (AA) in salvaging skeletal muscle atrophy, the underlying mechanisms concerning the activation of muscle stem cells and the regenerative process need further elucidation. In this study, we use a streptozotocin-induced Type 1 diabetes mouse model to study the effects of AA in mitigating the reduction in the myogenesis process and also try to elaborate on the anti-atrophic and anti-inflammatory properties of AA, which help to rescue the levels of sarcomeric protein. To carry out this study, male C57BL/6 mice (5-week-old) were divided into Control, diabetic (STZ) and AA-administered diabetic (STZ + AA) groups (n = 6 mice per group). The study involved a short-term treatment regime of 5 days. Muscle stem cell activation, inflammation, and muscle fiber integrity were assessed using molecular techniques. A global proteomic study provided insights into differential protein expression status. Histological analysis revealed the rescue of muscle cells at different stages of myogenesis and fiber integrity upon AA administration in diabetic mice. Moreover, the proteomic results supported the upregulation of stemness upon AA treatment as well. Additionally, it also showed the rescue of the sarcomeric protein repertoire. The findings suggest that AA holds myogenic properties, which stem from its role in activating the muscle stem cells, and this can be used as a potential therapeutic supplement for diabetic patients.

Keywords:  KLF15; arachidonic acid; muscle atrophy; muscle stem cell; muscle wasting; quantitative proteomics

DOI:  https://doi.org/10.1096/fj.202502321RR
Biochem Pharmacol. 2025 Sep 14. pii: S0006-2952(25)00591-X. [Epub ahead of print]242(Pt 2): 117326

Myokine-mediated muscle-organ interactions: Molecular mechanisms and clinical significance.

Jia Yi, Junyang Chen, Xinlei Yao, Zihao Zhao, Xinxin Niu, Xia Li, Jiacheng Sun, Yanan Ji, Tongxin Shang, Leilei Gong, Bingqian Chen, Hualin Sun.

  Regular exercise training preserves systemic homeostasis via coordinated multi-organ interactions, with skeletal muscle emerging as a pivotal effector organ and integrative signaling nexus. Recent breakthroughs in research have established the endocrine organ properties of skeletal muscle. Through contraction-induced release of myokines, skeletal muscle employs multimodal signaling mechanisms including autocrine, paracrine, and endocrine pathways, systematically elucidating the molecular basis of exercise benefits. This review innovatively proposes the "Myokine-mediated Multi-organ Metabolic Network" theory, comprehensively summarizing the role of myokines in mediating inter-organ crosstalk and dynamic communication mechanisms. These interactions involve skeletal muscle itself and multiple vital organs including heart, liver, lung, kidney, pancreas, brain, bone, skin, oral cavity, adipose tissue, intestine, stomach, mammary glands, ovaries, and prostate. Mechanistic insights elucidate that myokines function as pleiotropic signaling modulators, orchestrating multifaceted regulatory programs across six interconnected biological axes, including energy substrate flux and mitochondrial biogenesis, osteogenic differentiation and extracellular matrix remodeling, neuroplasticity and Blood-brain barrier (BBB) homeostasis, gut microbiota modulation, vascular endothelial function, and immunometabolic reprogramming within neoplastic niches. Notably, the multi-target regulatory capacity of myokines provides mechanistic insights into exercise-induced disease resistance. As "exercise-mimetic molecules," targeted delivery strategies of myokines provide novel therapeutic directions for metabolic diseases, neurodegenerative disorders, and cancer treatment. Crucially, three research frontiers demand prioritization: decoding spatiotemporal myokine secretion patterns; mapping receptor-ligand interaction networks across organs; and developing computational models predicting system-level responses to myokine modulation. Addressing these challenges will catalyze the translation of exercise physiology discoveries into precision therapeutics.

Keywords:  Crosstalk; Health and disease; Myokines; Skeletal muscles

DOI:  https://doi.org/10.1016/j.bcp.2025.117326
Physiol Rep. 2025 Sep;13(18): e70574

Unilateral isometric contraction induces REDD1 and suppresses insulin-stimulated mTORC1 and protein synthesis in non-contracted muscle of male mice.

Munkhtuul Munkh Amar, Taro Murakami.

  Skeletal muscle hypertrophy is promoted by mechanical loading and is associated with activation of mTORC1 signaling. While REDD1, a stress-responsive inhibitor of mTORC1, is typically downregulated in contracting muscle, we previously reported that unilateral isometric contraction increases REDD1 expression in the contralateral non-contracted muscle. The functional significance of this response remains unclear. This study tested whether REDD1 induction in non-contracted muscle attenuates anabolic signaling under insulin-stimulated conditions. Male C57BL/6J mice underwent unilateral isometric contraction of the right gastrocnemius via percutaneous electrical stimulation. Insulin was administered systemically to stimulate mTORC1 signaling and protein synthesis. Western blotting was used to assess REDD1 protein levels and phosphorylation of mTORC1 downstream targets and Akt. REDD1 protein was significantly elevated in non-contracted muscle following contraction. This was accompanied by reduced insulin-stimulated phosphorylation of S6K1 and 4E-BP1, as well as decreased puromycin incorporation, indicating suppressed protein synthesis. Insulin-stimulated Akt phosphorylation was unchanged, suggesting that the suppression occurred downstream or independently of Akt. These findings demonstrate that isometric contraction can impair insulin-stimulated mTORC1 signaling and protein synthesis in non-contracted muscle in male mice, potentially via REDD1 induction.

Keywords:  REDD1; insulin; isometric contraction; mTORC; muscle protein synthesis

DOI:  https://doi.org/10.14814/phy2.70574
Front Cell Dev Biol. 2025 ;13 1640275

Stem/progenitor cell-based therapy for Duchenne muscular dystrophy.

Tsukasa Tominari, Chaitra Sathyaprakash, Yoshitsugu Aoki.

  Duchenne muscular dystrophy is a genetic disease where loss of sarcolemma-associated protein, dystrophin, leads to progressive muscle wasting, and eventual loss of life from complications linked to cardiac deficits. Currently, numerous molecular therapies to restore dystrophin have entered clinical trials. However, the therapeutic benefits of these strategies in promoting tissue regeneration and reducing fibrosis remain limited. Stem/progenitor cell-based therapy in DMD patients is a promising strategy to promote muscle regeneration, though the conditions of transplantation and pre-treatments of numerous cell types are still being optimized. Several cell types with different properties and origins, such as myogenic stem/progenitor cells, mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs), have been studied for treating DMD. Myogenic stem/progenitor cells derived from healthy donors are expected to restore the number of myofibers as well as dystrophin expression in DMD muscles. MSCs derived from various tissues, including umbilical cord, have immunosuppressive properties and are expected to ameliorate DMD phenotypes in combination with other gene therapies. In this review, we will summarize the challenges that must be overcome to allow for successful DMD muscle tissue regeneration and review the latest findings in stem/progenitor cell-based DMD therapy. We will focus on the pre-conditioning of cells for replacement therapies and treatment of the disease niche to improve muscle fiber integration.

Keywords:  cardiac muscle; duchenne muscular dystrophy (DMD); dystrophin; skeletal muscle; stem cell therapies

DOI:  https://doi.org/10.3389/fcell.2025.1640275
J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70052

Mechanical Stimulation Induces Yap Mediated OCTN2 Transcription to Enhance Carnitine Metabolism in Sarcopenia.

Yahong Lu, Yu Bai, Weiqing Li, Zhiguo Zhou, Heihuan Lai, Xingyu Hu, Tao Yang, Chendi Wang, Yitao Chen, Keping Gan, Kechi Li, Haiwei Ma, Lin Shen, Dengwei He.

   BACKGROUND: Sarcopenia is a systemic skeletal muscle disease that seriously affects the health of the aged population. Exercise prevents sarcopenia, but the underlying mechanobiological and metabolic mechanisms need to be further investigated.
METHODS: Carnitine and organic cation transporter 2 (OCTN2) levels were assessed in humans and animals with sarcopenia. Skeletal muscle function and histomorphology were assessed in an animal model. Mitochondrial structure and function were assessed via MitoSox and JC-1 staining, seahorse assays and electron microscopy. Molecular mechanisms were assessed by Western blot analysis, qPCR, a luciferase reporter gene assay, chromatin immunoprecipitation and immunofluorescence in C2C12 myotubular cells.
RESULTS: A total of 66 patients were included in the study (Healthy group, % females: 44.74%, mean age: 67.40 ± 8.2, mean BMI: 24.7 ± 3.80 kg/m2; Sarcopenia group, % females: 39.29%, mean age: 71 ± 8.42, mean BMI: 23.1 ± 2.98 kg/m2). Serum carnitine levels decreased in sarcopenia patients (10 868 ± 3466 ng/mL vs. 8469 ± 2360 ng/mL, p < 0.01). Carnitine is an independent protective factor for sarcopenia (OR, 0.757; 95% CI 0.599-0.923, p = 0.0107). Carnitine and OCTN2 levels also decreased in the muscles of mice with dexamethasone-induced muscle atrophy (carnitine: -16.5%, p < 0.05) and aged mice (carnitine: -32.03%, p < 0.01). Suppressed expression of OCTN2 led to a decrease in muscle carnitine (2983 ± 466.3 ng/mL vs. 2517 ± 355.3 ng/mL, p < 0.05), as well as muscle atrophy in mice. Swimming exercise enhanced mice carnitine-dependent fatty acid oxidation and increased OCTN2 expression (OCTN2: +8.4%, p < 0.05). Knockdown of OCTN2 partially reduced this effect during swimming. Cellular experiments revealed that mechanical stimulation upregulated OCTN2 expression. OCTN2 knockdown impaired myotube formation and led to the disruption of the cellular mitochondrial structure. Further mechanistic studies showed that mechanical forces enhanced OCTN2 transcription and regulated carnitine metabolic homeostasis through the Yap/Tead4 pathway. Yap agonist XMU alleviated dexamethasone-induced muscle atrophy (grip: +13%, p < 0.05; cross-sectional area of the gastrocnemius muscle: +8%, p < 0.05). In a high-fat diet mouse model and in cellular experiments, carnitine supplement improved mitochondrial structure and alleviated mitochondrial dysfunction by reducing excessive lipid accumulation and thus altered myocyte fate.
CONCLUSION: Swimming and carnitine supplementation alleviated sarcopenia. The mechanism was closely related to the enhancement of OCTN2 expression after Yap activation and the enhancement of carnitine-mediated lipid metabolism. These findings reveal exercise regulates skeletal muscle by coupling mechanics and metabolism synergetically. We provide a new therapeutic strategy for sarcopenia.

Keywords:  OCTN2; Yap/Tead4; carnitine; fatty acids; lipid deposition; mechanical force; mitochondrial dysfunction; muscular atrophy

DOI:  https://doi.org/10.1002/jcsm.70052
EMBO Rep. 2025 Sep 16.

The muscle specific MEF2Dα2 isoform promotes muscle ketolysis and running capacity in mice.

Sushil Kumar, Xuan Ji, Hina Iqbal, Xiangnan Guan, Brittany Mis, Devanshi Dave, Suresh Kumar, Jacob Besler, Ranjan Dash, Zheng Xia, Ravi K Singh.

  During prolonged starvation and exhaustive exercise, when there is low availability of carbohydrates, the liver breaks down fatty acids to generate ketone bodies, which are utilized by peripheral tissues as an alternative fuel source. The transcription factor MEF2D undergoes regulated alternative splicing in the postnatal period to produce a highly conserved, muscle specific MEF2Dα2 protein isoform. Here, we discover that compared to WT mice, MEF2Dα2 exon knockout (Eko) mice display reduced running capacity and muscle expression of all three ketolytic enzymes: BDH1, OXCT1, and ACAT1. MEF2Dα2 Eko mice consistently show increased blood ketone body levels in a tolerance test, after exercise, and when fed a ketogenic diet. Lastly, using mitochondria isolated from skeletal muscle, Eko mice show reduced ketone body utilization compared to WT mice. Collectively, our findings identify a new role for the MEF2Dα2 protein isoform in regulating skeletal muscle ketone body oxidation, exercise capacity, and systemic ketone body levels.

Keywords:  Alternative Splicing; Ketone Body; MEF2 Transcription Factors; MExercise Metabolism

DOI:  https://doi.org/10.1038/s44319-025-00578-3
bioRxiv. 2025 Sep 12. pii: 2025.01.13.632729. [Epub ahead of print]

Embedding muscle fibers in hydrogel improves viability and preserves contractile function during prolonged ex vivo culture.

Leander A Vonk, Osman Esen, Daan Hoomoedt, Rajvi M N Balesar, Coen A C Ottenheijm, Tyler J Kirby.

Ex vivo culture of isolated muscle fibers can serve as an important model for in vitro research on mature skeletal muscle fibers. Nevertheless, this model has limitations for long-term studies due to structural loss and dedifferentiation following prolonged culture periods. This study aimed to investigate how ex vivo culture affects muscle fiber contraction and to improve the culture system to preserve muscle fiber morphology and sarcomere function. Additionally, we sought to determine which culture-induced changes can negatively affect muscle fiber contraction. We cultured isolated flexor digitorum brevis (FDB) muscle fibers in several conditions for up to 7 days, and investigated viability, morphology, the unloaded sarcomere shortening in intact fibers, along with force generation in permeabilized muscle fibers. In addition, we examined changes to the microtubule network. We found a time-dependent decrease in contractility and viability in muscle fibers cultured for 7 days on a laminin-coated culture dish (2D). Conversely, we found that culturing FDB muscle fibers in a low-serum, fibrin/Geltrex hydrogel (3D) reduces markers of muscle fiber dedifferentiation (i.e. sprouting), improves viability and retains contractility over time. We discovered that the loss of contractility of cultured muscle fibers was not the direct result of reduced sarcomere function but may be related to changes in the microtubule network. Collectively, our findings highlight the importance of providing muscle fibers with a 3D environment during ex vivo culture, particularly when testing pharmacological or genetic interventions to study viability or contractile function.

DOI: https://doi.org/10.1101/2025.01.13.632729
Radiol Oncol. 2025 09 01. 59(3): 293-300

Radiation-induced impairment of skeletal muscle regeneration.

Maja Cemazar, Mihaela Jurdana.

   BACKGROUND: Radiotherapy is a cornerstone of treatment for various cancers, but often causes collateral damage to surrounding healthy tissue, including skeletal muscle. Ionizing radiation leads to oxidative stress and inflammation, which impairs the regenerative capacity of muscle tissue. Irradiation reduces the number and functionality of satellite cells and disrupts the tightly regulated processes of myogenesis and tissue remodelling. In addition, irradiation alters the muscle microenvironment by promoting fibrosis and vascular damage, which further impedes effective regeneration. Cytokine signalling pathways are also dysregulated following irradiation, contributing to impaired activation and differentiation of satellite cells.
CONCLUSIONS: There is evidence that factors such as melatonin and growth factors can improve muscle regeneration. Understanding the molecular and cellular mechanisms underlying the impairment of muscle regeneration after radiotherapy is crucial for the development of targeted strategies to mitigate side effects and improve patients' quality of life. Overall, the preservation and restoration of muscle function in irradiated tissue remains a critical challenge that requires multidisciplinary approaches.

Keywords:  melatonine; muscle microenvironment; muscle regeneration; radiotherapy; skeletal muscle

DOI:  https://doi.org/10.2478/raon-2025-0048
Shock. 2025 Sep 05.

P2X7 Receptor acts as a novel target for ameliorating Sepsis-induced skeletal muscle atrophy in mice model.

Yukun Liu, Qinxin Liu, Zhikai Xu, Xuan Zhao, Fan Yang, Zhanfei Li, Xiangjun Bai, Jian Yang, Yuchang Wang.

   BACKGROUND AND OBJECTIVE: Sepsis, a systemic inflammatory syndrome, frequently leads to substantial skeletal muscle loss and dysfunction, severely impairing patient prognosis. The P2X7 receptor is an ATP-gated cation channel implicated in inflammation and cell death. Although its role in the immune system has been extensively studied, its expression profile and pathogenic mechanism in sepsis-induced skeletal muscle atrophy remain unclear. This study aimed to investigate the functional role of the P2X7 receptor in sepsis-associated muscle injury and its potential as a therapeutic target.
METHODS: A murine sepsis model was established using cecal ligation and puncture (CLP) surgery. Temporal changes in P2X7 receptor expression in the gastrocnemius (GP) and tibialis anterior (TA) muscles were assessed. Functional studies were performed using P2X7 knockout (P2X7⁻/⁻) mice and the P2X7-specific antagonist A-740003. Skeletal muscle atrophy, inflammatory responses, and activation of the NLRP3 inflammasome signaling pathway were systematically evaluated through Western blotting, qPCR, hematoxylin-eosin staining, muscle fiber cross-sectional area analysis, and measurement of inflammatory cytokines.
RESULTS: In the CLP-induced sepsis model, P2X7 receptor expression in both GP and TA muscles was upregulated in a time-dependent manner. P2X7 gene deletion significantly attenuated body weight loss, muscle mass reduction, and muscle fiber atrophy, restored grip strength, and suppressed the expression of atrophy-related genes (Myostatin, Atrogin-1, and MuRF1). Moreover, it markedly reduced IL-6, IL-18, and IL-1β levels in both skeletal muscle and plasma, indicating an anti-inflammatory effect. P2X7 deficiency also significantly inhibited the expression of NLRP3 inflammasome components, caspase-1, and GSDMD, thereby blocking the pyroptosis signaling pathway. Pharmacological inhibition with A-740003 showed dose-dependent mitigation of muscle atrophy, further supporting the therapeutic potential of targeting P2X7.
CONCLUSION: The P2X7 receptor contributes to sepsis-induced skeletal muscle atrophy by promoting inflammation and muscle protein degradation through activation of the NLRP3 inflammasome and pyroptosis pathways. Genetic or pharmacological inhibition of P2X7 significantly alleviates muscle damage and functional loss. These findings provide strong experimental evidence supporting P2X7 as a potential therapeutic target for sepsis-associated myopathy.

Keywords:  A-740003; NLRP3; P2X7; sepsis; sepsis-induced myopathy

DOI:  https://doi.org/10.1097/SHK.0000000000002703
Ecotoxicol Environ Saf. 2025 Sep 12. pii: S0147-6513(25)01389-2. [Epub ahead of print]303 119044

Atrazine exposure induces skeletal muscle atrophy: Multi-omics insights into mechanisms and therapeutic targets.

Jianguo Tao, Jiaxuan Gu, Maomao Miao, Guo-Bo Chen, Xueqin Hu, Sai Yao, Ou Wu, Taotao Xu, Huan Luo, Hongting Jin, Chengliang Wu, Peijian Tong, Hongfeng Ruan, Xiangjiao Yi, Hou-Feng Zheng.

  Atrazine (ATZ), a frequently used herbicide, has well-documented toxicities in various organisms, yet its specific impact on skeletal muscle remains largely uncharted. Here, we found that ATZ inhibited myotube formation in C2C12 myoblasts and decreased both body weight and the cross-sectional areas of type IIA, IIB, and IIX myofibers in mice. Furthermore, ATZ drove muscle fiber shifting from mixed oxidative/glycolytic type IIA to fast-glycolytic type IIB, reduced satellite stem cell abundance, and contributed to excessive lipid accumulation. Mechanistically, transcriptomic analyses indicated that ATZ triggered inflammation, oxidative stress, adipogenesis, and protein degradation, as evidenced by elevated ROS, augmented NF-κB pathway, and disrupted protein homeostasis. By integrating transcriptomic data with eQTL and grip strength GWAS findings from 454,473 individuals, and applying Mendelian randomization and Bayesian colocalization analyses, we pinpointed 14 genes that were both dysregulated by ATZ and causally linked to muscular strength. Further interrogation of single-cell/nucleus RNA-sequencing data revealed cell type-specific patterns of 10 reasonable causal genes (Jund, Limd2, Ppm1j, Procr, Cdo1, Irs1, Kif1b, Nav1, Nexn, Peak1), highlighting the multifaceted cellular processes underlying ATZ-inflicted muscle damage. Notably, Morroniside, with anti-inflammatory and antioxidant properties, rescued several potential therapeutic targets (Limd2, Jund, Irs1, Kif1b, Peak1, Nav1) and C2C12 myotubes from ATZ-induced atrophy. Collectively, our study sheds light on the effects and molecular underpinnings of ATZ-mediated skeletal muscle toxicity and brings forward viable therapeutic targets and strategy. The multi-omics approach offers a robust framework for translating findings from cell/animal models to human relevance in toxicological research.

Keywords:  Atrazine; GWAS; Inflammation; Mendelian randomization; Morroniside; Protein homeostasis; Skeletal muscle atrophy

DOI:  https://doi.org/10.1016/j.ecoenv.2025.119044
Development. 2025 Sep 17. pii: dev.204771. [Epub ahead of print]

Differentially expressed fusogens specify myocyte states to drive myogenesis.

Sarah Nahlé, Awais Javed, Loïck Joumier, Yacine Kherdjemil, Julie Sitolle, Konstantin Khetchoumian, Yash Parekh, Wojciech Krezel, Mohan Malleshaiah, Fabien Le Grand, Michel Cayouette, Jean-François Côté.

  During myogenesis, myocyte fusion leads to the formation of multinucleated muscle fibers but how exactly this process is initiated remains poorly understood. Here, we performed single-cell RNA sequencing on mouse somites from E9.5-11.5 embryos, revealing multiple differentiation states during primary myogenesis. Among these, we identified two unexpected myocyte populations: one expressing both Myomaker (Mymk) and Myomixer (Mymx) (termed Mc1) and another expressing only Mymk (termed Mc2). Fluorescent in situ hybridization demonstrated that both populations are mononucleated and co-exist within the same somites, with only Mc1 persisting during secondary myogenesis. Lineage tracing using Mymx:Cre; RosaTdT mice demonstrated that the Mc2 cells arise from the Mc1. Mechanistically, we show that Mef2 and Rxr factors positively and negatively regulate Mymx expression, respectively. Additionally, RXRG interacts with MYOD1 and MYOG, modulating their transcriptional activity in luciferase assays. Collectively, our findings uncover two populations among the myocytes that drive primary and secondary fiber formation, challenging the traditional view of vertebrate muscle precursor homogeneity.

Keywords:  Differentiation dynamics; Myocyte; Myogenesis; Myomaker; Myomixer; Skeletal muscle

DOI:  https://doi.org/10.1242/dev.204771
J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70027

High-Calorie Diet During Pregnancy Leads to Muscular Fibrosis and Neuromuscular Damage in Offspring Mice.

Jun Seok Son, Song Ah Chae, Yoon Ha Chun, Hongyang Wang, Zhihua Jiang, Min Du.

   BACKGROUND: Sarcopenia, recognized as an age-related loss of muscle mass and function, is a critical risk for geriatric health. We previously demonstrated that maternal high-fat diet (HFD) suppresses mitochondrial biogenesis during fetal skeletal muscle development, but the longitudinal effect of maternal HFD challenge on offspring muscle sarcopenia and fitness impairment remains unclear. Mitochondrial polymerase γ (PolG) mutation accelerates mitochondrial DNA mutations and leads to premature aging.
METHODS: To determine the mechanisms underlying the longitudinal effect of maternal HFD challenge on offspring sarcopenia and aging, heterozygote mitochondrial polymerase γ mutated (PolgAmut/+) female mice were fed either a control diet (CD) or HFD during pregnancy, which were mated with heterozygote PolgA male mice. Thus, we had four experimental groups: maternal CD (M-CD) + WT, M-CD + PolgAmut, M-HFD + WT and M-HFD + PolgAmut. Six-month-old offspring mice were utilized for testing metabolic health, maximal muscle strength and cardiorespiratory fitness capacity. Then, 9-month-old offspring mice were used for biochemical and histochemical analyses.
RESULTS: Maternal high-calorie diet during pregnancy decreased offspring muscle strength and cardiorespiratory function (p < 0.05), which were associated with loss of muscle mass (p < 0.05). These adverse outcomes were most dramatic in M-HFD with PolG mutation (p < 0.05). Maternal HFD challenge activated muscle atrophy signalling, including MuRF1 and Atrogin-1 (p < 0.05), which were worsened in PolgA mice (p < 0.05). Furthermore, M-HFD increased the accumulation of intramuscular fibrosis in PolgA offspring (p < 0.05). In addition, M-HFD increased the risk of neuromuscular damage by attenuating GABAA receptor pathway in PolgA mice (p < 0.05).
CONCLUSIONS: Maternal high-calorie diet during pregnancy induced offspring muscle atrophy and intramuscular fibrosis, especially with PolG mutation, underscoring mitochondrial dysfunction in linking maternal HFD to offspring premature aging.

Keywords:  aging; maternal high‐fat diet; mitochondria; pregnancy; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.70027
Neuropathol Appl Neurobiol. 2025 Oct;51(5): e70038

Quantification of Exercise-Induced Sarcomeric Damage in R349P Desmin Knock-In Mice: A New Approach in Myofibrillar Myopathy Research.

Christian Holtzhausen, Dorothea Schultheis, Carolin Berwanger, Julia Schuld, Ursula Schlötzer-Schrehardt, Marion Riehl-Nestler, Sabrina Batonnet-Pichon, Alain Lilienbaum, Esther Mahabir, Peter F M van der Ven, Dieter O Fürst, Rolf Schröder, Christoph S Clemen.

   AIMS: The classical morphological hallmarks of the clinically and genetically diverse group of human myofibrillar myopathies are signs of myofibrillar degeneration and desmin-positive protein aggregates. The local sarcomeric enrichment of filamin-C and xin actin-binding repeat-containing proteins 1 and 2 (xirp 1 and xirp 2) is a marker of myofibrillar damage. This work aimed to (i) address filamin-C- and xirp 1/2-positive sarcomeric lesions in desminopathy mouse models, (ii) develop an approach to quantifying xirp 1/2-positive sarcomeric lesions, and (iii) study the effects of acute physical exercise on sarcomeric lesion formation in R349P desmin knock-in mice, which are a model of human R350P desminopathy.
METHODS: Sarcomeric lesions were visualised by xirp 1/2 and filamin-C immunofluorescence in soleus muscles from R349P and R405W desmin knock-in, desmin knock-out and W2711X filamin-C knock-in mice. The open-source software QuPath was used to analyse xirp 1/2 confocal immunofluorescence images of soleus muscle from nonexercised and treadmill-exercised R349P desmin knock-in mice.
RESULTS: Filamin-C and xirp 1/2 stained muscles revealed the presence of congenerous sarcomeric lesions in heterozygous and homozygous R349P and R405W desmin knock-in, homozygous desmin knock-out and heterozygous and homozygous W2711X filamin-C knock-in mice. Quantitative analysis of R349P desmin knock-in mice showed (i) significantly more lesions in nonexercised heterozygous mice, with an even more pronounced increase in homozygous animals, as compared to wild-type, and (ii) a significant increase in sarcomeric lesions per mm2 in heterozygous mice and wild-type siblings subjected to strenuous treadmilling.
CONCLUSIONS: A QuPath workflow to quantify sarcomeric lesions using xirp 1/2 immunofluorescence images showed augmented densities of lesions in R349P desminopathy mice and after treadmill exercise. Eccentric and high-intensity physical activity may exhibit a disease-promoting effect on skeletal muscles in desminopathy.

Keywords:  FLNC; desmin; desminopathy; exercise‐induced muscle damage; myofibrillar myopathies; quantitation of sarcomeric lesions; treadmill exercise; xirp

DOI:  https://doi.org/10.1111/nan.70038
Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101564

Nanoparticle delivery of AMPK activator 991 prevents its toxicity and improves muscle homeostasis in Duchenne muscular dystrophy.

Ilaria Andreana, Ananga Ghosh, Mathieu Repellin, Anita Kneppers, Sabrina Ben Larbi, Federica Tifni, Aurélie Fessard, Marion Martin, Jacqueline Sidi-Boumedine, David Kryza, Barbara Stella, Silvia Arpicco, Claire Bordes, Yves Chevalier, Julien Gondin, Bénédicte Chazaud, Rémi Mounier, Giovanna Lollo, Gaëtan Juban.

  Muscular dystrophies, such as Duchenne muscular dystrophy (DMD), are caused by permanent muscle injuries leading to chronic inflammation, with macrophages harboring an altered inflammatory profile contributing to fibrosis through the secretion of transforming growth factor β1 (TGF-β1). We previously showed that AMP-activated protein kinase (AMPK) activation reduces TGF-β1 secretion by macrophages and improves muscle homeostasis and muscle force in a DMD mouse model. However, direct AMPK activators like compound 991 show strong adverse effects in vivo. To overcome this toxicity, we encapsulated 991 into biodegradable polymeric poly(lactic-co-glycolic) acid (PLGA) nanoparticles for in vivo delivery. We show that 991-loaded PLGA nanoparticles retained drug activity on fibrotic macrophages in vitro and in vivo. In the D2-mdx DMD mouse model, intravenously injected PLGA nanoparticles reached macrophages in gastrocnemius and diaphragm muscles, two severely affected muscles in this model, but not in heart and quadriceps. Chronic intravenous injections of 991-loaded PLGA nanoparticles decreased inflammation in both gastrocnemius and diaphragm, which was associated with TGF-β1 level and fibrosis reduction and increase in myofiber size and muscle mass in the gastrocnemius, without toxicity. These results demonstrate that nanomedicine is an efficient strategy to deliver AMPK activators in vivo to target inflammation and improve the dystrophic muscle phenotype in the gastrocnemius.

Keywords:  AMPK; Duchenne muscular dystrophy; PLGA nanoparticles; chronic inflammation; fibrosis

DOI:  https://doi.org/10.1016/j.omtm.2025.101564
J Bone Metab. 2025 Aug;32(3): 167-179

Latest Updates on Sarcopenia and Cachexia: Insights from the 17th Sarcopenia, Cachexia, and Wasting Disorders Conference.

Hyunwoo Park, Hyeon Su Kim, Bon-Sang Gu, Hyunbin Kim, Jun-Il Yoo.

  The 17th Sarcopenia, Cachexia, and Wasting Disorders Conference, held from December 6 to 8, 2024, in Washington, DC, showcased groundbreaking advancements in understanding and managing muscle wasting conditions. Drawing on the lecture notes and presentations of internationally recognized experts who spoke at the meeting, this review highlights key insights and recent developments discussed during the conference. This review focuses on sarcopenia, cancer cachexia, and other wasting disorders linked to chronic diseases. Key discoveries included the identification of the Macroautophagy and YouTH Optimizer pathway in muscle regulation, the role of ectodysplasin A2 receptor-nuclear factor-κB-inducing kinase signaling in muscle atrophy, and the impact of mitochondrial dysfunction on systemic health. Advancements in diagnostic tools, including artificial intelligence-powered imaging and novel biomarkers, are transforming the detection and management of these conditions. Emerging therapeutic strategies, such as glucagon-like peptide 2-based treatments, selective androgen receptor modulators, and cytokine inhibitors, are reshaping the therapeutic landscape. The conference underscored the importance of precision medicine, integrating molecular insights with personalized care approaches, and emphasized multidisciplinary rehabilitation to optimize patient outcomes. The conference also highlighted promising clinical advancements, including the HIPGEN trial on placental-expanded stromal cells for muscle regeneration in hip fracture patients and the ponsegromab study targeting growth/differentiation factor-15 inhibition to mitigate cancer cachexia-associated muscle wasting. This review highlights the integration of basic science, innovative diagnostics, and clinical applications as a promising framework for addressing the complex challenges posed by muscle-wasting disorders. As the field progresses, these insights offer hope for improving the quality of life and survival of affected patients.

Keywords:   Cachexia; Clinical trials as topic; Sarcopenia; Biomarkers

DOI:  https://doi.org/10.11005/jbm.25.867
bioRxiv. 2025 Sep 04. pii: 2025.09.01.673443. [Epub ahead of print]

Baculovirus-mediated gene transfer enables functional expression of the PIEZO1 ion channel in isolated muscle satellite cells.

Akira Murakami, Ayuno Masuda, Takumi Hirakawa, Kotaro Hirano, Masaki Tsuchiya, Yusuke Ono, Takashi Murayama, Yuji Hara.

Primary tissue stem cells are useful not only for basic cell biological research but also for therapeutic applications: however, their broader utility is often limited by technical challenges, such as a low efficiency of exogenous gene expression. PIEZO1 is a large mechanosensitive ion channel that plays an important role in muscle-resident stem cells, known as muscle satellite cells (MuSCs), during muscle regeneration. In this study, we developed a method for the ectopic expression of PIEZO1 in isolated MuSCs. Using a baculovirus vector system, we expressed PIEZO1 in myoblast C2C12 cells. Following optimization of the infection condition, we achieved robust PIEZO1 expression in isolated MuSCs during activated and differentiated states, with appropriate subcellular localization and ion channel activity. Importantly, the baculovirus-mediated PIEZO1 expression restored the reduced proliferative capacity of Piezo1 -deficient MuSCs to a level comparable to wild-type cells, indicating that the exogenously expressed PIEZO1 is functionally equivalent to the endogenous protein. Overall, we established an efficient method for the transfer of the Piezo1 gene into isolated MuSCs, which should provide a versatile platform to study other large proteins in MuSCs.
Summary Statement: A baculovirus-based method was developed, enabling robust and functional PIEZO1 expression in isolated muscle satellite cells and providing a platform to study large proteins in isolated stem cells.

DOI: https://doi.org/10.1101/2025.09.01.673443
Aging (Albany NY). 2025 Sep 11. 17

Roles of plasminogen activator inhibitor-1 in aging-related muscle and bone loss in mice.

Takashi Ohira, Naoyuki Kawao, Yuya Mizukami, Kiyotaka Okada, Akihito Nishikawa, Hisatoshi Yamao, Ayaka Yamada, Hiroshi Kaji.

  Aging-related sarcopenia and osteoporosis are musculoskeletal disorders characterized by accelerated muscle and bone loss. Plasminogen activator inhibitor-1 (PAI-1), a fibrinolysis inhibitor, is involved in various pathological conditions, including sarcopenia and osteoporosis; however, its roles in aging-related sarcopenia and osteoporosis have yet to be fully investigated. Therefore, we investigated the roles of PAI-1 in aging-related sarcopenia and osteoporosis using PAI-1-gene-deficient and wild-type mice. Aging-related changes in muscle and bone were assessed by comparing the values in 24-month-old mice to those in 6-month-old mice. Regardless of sex, differences in muscle and bone parameters were observed between 24-month-old and 6-month-old mice. Aging increased PAI-1 expression in the gastrocnemius and soleus muscles of both female and male mice. PAI-1 deficiency significantly blunted aging-related decreases in lower limb muscle mass, muscle tissue weights, and grip strength in female mice but not in males. Moreover, PAI-1 deficiency significantly blunted aging-related cortical bone loss at the femurs and tibias of female but not male mice. These results indicate that PAI-1 is partly involved in aging-related sarcopenia and osteopenia in female mice, although the corresponding mechanisms remain unknown.

Keywords:  aging; osteoporosis; plasminogen activator inhibitor-1; sarcopenia; sex

DOI:  https://doi.org/10.18632/aging.206318
Int J Sports Med. 2025 Sep 16.

Exercise-Induced Epigenetic Modifications: Implications for Healthy Aging.

Qi Yang, Yue Hu, Bing Zhang, Weihao Hong.

Aging is a complex biological process driven by the dynamic interplay among genetic, environmental, and lifestyle factors. Advances in epigenetics have significantly deepened our understanding of the molecular mechanisms underlying aging, underscoring the critical roles of reversible modifications such as DNA methylation, histone modifications, and non-coding RNA regulation. Emerging evidence suggests that exercise is a potent modulator of these epigenetic processes, capable of reshaping the epigenetic landscape to restore cellular homeostasis, modulate gene expression, and enhance physiological resilience. This review systematically synthesizes current knowledge on how exercise modulates epigenetic mechanisms implicated in aging and delineates the distinct epigenetic adaptations induced by variations in exercise modality, intensity, and duration. By integrating these molecular insights, this review provides a comprehensive mechanistic framework linking exercise-induced epigenetic remodeling to healthy aging, and underscores exercise as a promising intervention to counteract aging-related functional decline and disease progression.

DOI: https://doi.org/10.1055/a-2702-4789
medRxiv. 2025 Sep 04. pii: 2025.09.02.25334959. [Epub ahead of print]

Transcriptome and microRNAome profiling of human skeletal muscle in pancreatic cancer cachexia.

Ashok Narasimhan, Xiaoling Zhong, Brittany R Counts, Andrew Young, Sha Cao, Jun Wan, Sheng Liu, Leonidas G Koniaris, Teresa A Zimmers.

Background and Aims: Over 80% of patients with pancreatic cancer experience cachexia, characterized by severe muscle and fat loss. While all the mechanistic understanding comes from preclinical models, the translatable nature of these findings to humans remains a critical gap due to the limited knowledge of human cachexia biology.
Methods: We generated matched gene and microRNA profiles from rectus abdominis muscle of 55 pancreatic ductal adenocarcinoma and 18 control subjects. Differentially expressed genes and microRNAs were identified at 1.5-fold change and p<0.05.
Results: Gene expression results revealed a striking sex-specific difference at the expression and pathway levels. In both sexes, co-expression gene network analysis identified more significant modules and hub genes at 1-month of weight loss than the traditionally used six months, suggesting that gene alterations may be more dynamic in the early stages of the disease progression. When comparing hub genes from humans to experimental models of cachexia, genes such as RELA, DDX21, WDR75, PTPN1, and CRIP3 exhibited similar patterns of expression, suggesting their potential role in cachexia. microRNAs also exhibited sex-specific expression. Although several common miRNAs were identified between sexes, their gene targets differed, indicating that microRNAs may regulate gene targets in a sex-specific manner.
Conclusions: The dataset can serve as a resource for validating preclinical findings and exploring previously unexplored molecules in cachexia. Future studies will functionally characterize the role of the hub genes and microRNAs in cachexia. This is the first study to identify sex-specific genes and microRNAs from a single cancer type.

DOI: https://doi.org/10.1101/2025.09.02.25334959
Elife. 2025 Sep 17. pii: RP94288. [Epub ahead of print]13

A novel mouse model for LAMA2-related muscular dystrophy with analysis of molecular pathogenesis and clinical phenotype.

Dandan Tan, Yidan Liu, Huaxia Luo, Qiang Shen, Xingbo Long, Luzheng Xu, Jieyu Liu, Nanbert A Zhong, Hong Zhang, Hui Xiong.

  Our understanding of the molecular pathogenesis of LAMA2-related muscular dystrophy (LAMA2-MD) requires improving. Here, we report the phenotype, neuropathology, and transcriptomics data (scRNA-seq and bulk RNA-seq) of a new Lama2 knockout mouse (dyH/dyH) which was created based on the human LAMA2-MD mutation hotspot region using CRISPR-Cas9. The dyH/dyH mice presented a severe phenotype with muscular dystrophy. Mouse brain scRNA-seq showed that Lama2 gene was expressed predominantly and specifically in vascular and leptomeningeal fibroblasts and vascular smooth muscle cells, and weakly in astrocytes in wild-type mouse. Laminin α2 expression on the cortical surface was observed with immunofluorescence. In dyH/dyH, Lama2 expression was decreased in those cell types, which might be associated with the disruption of gliovascular basal lamina assembly. Additionally, transcriptomic investigation of muscles showed 2020 differentially expressed genes, mainly associated with the impaired muscle cytoskeleton and development. In summary, this study provided potentially useful information for understanding the molecular pathogenesis of LAMA2-MD.

Keywords:  Lama2; blood-brain barrier; mouse; muscular dystrophy; neuroscience; novel mouse model; single-cell RNA sequencing; transcriptomic study

DOI:  https://doi.org/10.7554/eLife.94288