bims-musmir Biomed News
on microRNAs in muscle
Issue of 2025–08–10
twelve papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway



  1. Physiol Rep. 2025 Aug;13(15): e70497
      Disuse drives rapid muscle atrophy and metabolic dysfunction. This study aimed to characterize phenotypic and transcriptomic skeletal muscle changes in middle-aged individuals during disuse and rehabilitation. Eleven healthy middle-aged adults (6 males, 5 females; age; 57 ± 5 years) underwent 7 days of unilateral lower limb suspension (ULLS). Following disuse, participants participated in a rehabilitation program consisting of either a lower-body resistance exercise (RE) or walking control (WC) three times weekly for 2 weeks. Bilateral skeletal muscle biopsies were collected at Day 0 and Day 7 of disuse and 2 h post-exercise on Days 7, 9, 11, and 21. Strength testing was conducted, and RNA sequencing was performed on muscle samples. Seven days of disuse reduced knee extension strength (14%; p < 0.05) and isometric force (13%; p < 0.05). Over-representation analysis revealed a downregulation of mRNAs related to cellular respiration and NADH dehydrogenase complex assembly. Resistance exercise induced robust, but different, transcriptional changes in both disuse- and control-legs. Walking had minimal effect on the muscle transcriptome. We conclude that 7 days of disuse reduced leg strength, decreased mitochondrial gene expression, and increased inflammation and apoptosis-related genes. We also conclude that resistance exercise enhanced recovery from disuse by improving strength, associated with significant transcriptomic changes.
    Keywords:  aging; disuse atrophy; resistance exercise; transcriptomics
    DOI:  https://doi.org/10.14814/phy2.70497
  2. BMC Cancer. 2025 Aug 04. 25(1): 1265
      
    Keywords:  Biological sex; Consensus; Neoplasms; Quality of life; Retrospective studies; Weight loss
    DOI:  https://doi.org/10.1186/s12885-025-14555-5
  3. Exp Physiol. 2025 Aug 05.
      Skeletal muscle adaptation to contractile activity is modulated by redox signalling, primarily through reactive oxygen species (ROS) such as hydrogen peroxide (H2O2). Early research framed ROS as deleterious byproducts of exercise, but subsequent studies have established their roles as signalling molecules involved in mitochondrial biogenesis, stress responses and metabolic regulation. Central to this process appear to be peroxiredoxins (Prdxs), particularly Prdx2, which current evidence suggests mediate redox relays by sensing physiological H2O2 levels and initiating transcriptional programs. Our recent findings demonstrate that low levels of H2O2, or electrically induced contractions, rapidly oxidise Prdx1, Prdx2 and Prdx3 in mouse muscle fibres. Transcriptomic analysis of human skeletal muscle myotubes confirmed that Prdx2 is essential for upregulating mitochondrial genes in response to H2O2 or contraction. With ageing, skeletal muscle exhibits impaired redox signalling with elevated ROS levels. Using an ageing mouse model, we observed diminished Prdx2 oxidation during contraction, suggesting redox signalling dysfunction. This impaired response likely contributes to sarcopenia by blunting the adaptive capacity of aged muscle. Our findings emphasise the importance of redox homeostasis (not merely ROS suppression) in maintaining muscle health. Understanding the nuanced role of ROS and Prdxs in exercise adaptation and ageing could inform therapeutic strategies aimed at restoring redox-sensitive signalling to preserve muscle function across the lifespan.
    Keywords:  NMJ; hydrogen peroxide; mitochondria; motor neuron
    DOI:  https://doi.org/10.1113/EP092458
  4. bioRxiv. 2025 Aug 02. pii: 2025.07.30.667744. [Epub ahead of print]
      Sarcopenia, the age-related loss of muscle strength and mass, contributes to adverse health outcomes in older adults. While exercise mitigates sarcopenia by transiently activating calcium (Ca 2+ )- and reactive oxygen species (ROS)-dependent signaling pathways that enhance muscle performance and adaptation, these same signals become chronically elevated in aged skeletal muscle and promote functional decline. Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is a key transducer of both Ca 2+ and ROS signals during exercise. Here we show that CaMKII is chronically activated in aged muscles, promoting muscle dysfunction. Muscle-specific expression of a constitutively active CaMKII construct in young mice recapitulates features of aging muscles, including impaired contractility, progressive atrophy, mitochondrial disorganization, formation of tubular aggregates, and an older transcriptional profile characterized by the activation of inflammatory and stress response pathways. Mediation analysis identified altered heme metabolism as a potential mechanism of CaMKII-induced weakness, independent of muscle atrophy. Conversely, partial inhibition of CaMKII in aged muscle improved contractile function and shifted the transcriptome toward a more youthful state without inducing hypertrophy. These findings identify chronic CaMKII activation as a driver of functional and molecular muscle aging and support the concept that CaMKII exemplifies antagonistic pleiotropy, whereby its beneficial roles in promoting muscle performance and adaptation during youth may incur deleterious consequences in aging. We propose that persistent CaMKII activation in aged skeletal muscle reflects unresolved cellular stress and promotes maladaptive remodeling. Enhancing physiological reserve capacity through exercise, in combination with temporally targeted CaMKII inhibition, may help restore adaptive CaMKII signaling dynamics and preserve muscle function in aging.
    DOI:  https://doi.org/10.1101/2025.07.30.667744
  5. Skelet Muscle. 2025 Aug 07. 15(1): 20
       BACKGROUND: The RNA-binding protein hnRNPK is essential for animal growth and development, with a particular emphasis in myogenesis. Despite its importance, the precise mechanisms by which hnRNPK influences skeletal muscle physiology and development remain inadequately characterized.
    METHODS: To explore its regulatory function, we developed a Myf5-cre-mediated myoblast precursor-specific knockout mouse model (Hnrnpk mKO), an Acta1-CreEsr1-mediated myofiber-specific inducible knockout mouse model (Hnrnpk aKO), and an AAV9-mediated skeletal muscle-specific overexpression mouse model (AAV9-hnRNPK). Morphological alterations in skeletal muscle were assessed using hematoxylin and eosin (HE) staining subsequent to hnRNPK knockout or overexpression. Global gene expression changes in the tibialis anterior (TA) muscle were assessed via RNA sequencing (RNA-seq). Furthermore, reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blot analysis, immunofluorescence, immunohistochemistry, co-immunoprecipitation (Co-IP), dual luciferase analysis, and reactive oxygen species (ROS) detection were utilized to elucidate the molecular mechanisms by which hnRNPK contributes to skeletal muscle development.
    RESULTS: Our findings indicate that the ablation of hnRNPK in myoblast precursors significantly impairs muscle development, disrupts fetal myogenesis, and results in embryonic lethality. In adult mice, both the loss and gain of hnRNPK function led to reduced muscle mass, decreased fiber size, and compromised skeletal muscle homeostasis. Importantly, the knockout of hnRNPK had a more substantial impact on skeletal muscle development compared to its overexpression, with myofiber-specific knockout leading to mortality within two weeks. Mechanistically, hnRNPK deficiency was associated with increased apoptosis and muscle atrophy, characterized by elevated expression of genes involved in apoptosis, muscle atrophy, and protein catabolism, along with impaired muscle contraction and extracellular matrix (ECM) organization. Conversely, hnRNPK overexpression was correlated with enhanced ferroptosis pathway and improved ECM organization, but was also associated with reduced oxidative phosphorylation and protein synthesis. The overexpression likely promotes ferroptosis via the hnRNPK/P53/Slc7a11/Gpx4 pathway, thereby accelerating muscle aging and reducing muscle mass.
    CONCLUSION: In conclusion, our findings underscore the critical importance of precise hnRNPK expression levels in maintaining skeletal muscle health. Both deficiency and overexpression of hnRNPK disrupt skeletal muscle development, highlighting its pivotal role in muscle physiology.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  HnRNPK; Knockout; Mice; Muscle atrophy; Overexpression; Skeletal muscle
    DOI:  https://doi.org/10.1186/s13395-025-00393-3
  6. bioRxiv. 2025 Jul 27. pii: 2025.07.23.666188. [Epub ahead of print]
      The N-degron pathway contributes to proteolysis by targeting N-terminal residues of destabilized proteins via E3 ligases that contain a UBR-box domain. Emerging evidence suggests the UBR-box family of E3 ubiquitin ligases (UBR1-7) are involved in the positive regulation of skeletal muscle mass. The purpose of this study was to explore the role of UBR-box E3 ubiquitin ligases under enhanced protein synthesis and skeletal muscle growth conditions. Cohorts of adult male mice were electroporated with constitutively active Akt (Akt-CA) or UBR5 RNAi constructs with a rapamycin diet intervention for 7 and 30 days, respectively. In addition, the UBR-box family was studied during the regrowth phase post nerve crush induced inactivity. Skeletal muscle growth with Akt-CA or regrowth following inactivity increased protein abundance of UBR1, UBR2, UBR4, UBR5 and UBR7. This occurred with corresponding increases in Akt-mTORC1/S6K and MAPK/p90RSK signaling and protein synthesis. The increases in UBR-box E3s, ubiquitination, and proteasomal activity occurred independently of mTORC1 activity and were associated with increases in markers related to autophagy, ER-stress, and protein quality control pathways. Finally, while UBR5 knockdown (KD) evokes atrophy, it occurs together with hyperactivation of mTORC1 and protein synthesis. In UBR5 KD muscles, we identified an increase in protein abundance for UBR2, UBR4 and UBR7, which may highlight a compensatory response to maintain proteome integrity. Future studies will seek to understand the role of UBR-box E3s towards protein quality control in skeletal muscle plasticity.
    New and Noteworthy: Novel UBR-box E3 ubiquitin ligases are responsive to heightened protein synthesis and alterations in skeletal muscle mass and fiber size, in order to maintain proteome integrity.
    DOI:  https://doi.org/10.1101/2025.07.23.666188
  7. Brain Behav Immun. 2025 Jul 31. pii: S0889-1591(25)00299-5. [Epub ahead of print] 106065
      Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by substantial degeneration of dopaminergic neurons in the substantia nigra and dopamine depletion in the striatum, leading to debilitating motor and non-motor impairments. Recent studies provide clues on the pathogenic role of DNA damage in age-related neurodegenerative diseases, but the molecular mechanisms of DNA damage response in PD remain poorly understood. We found that the accumulation of DNA double-strand breaks (DDSBs), and/or DNA repair deficits, are key in the pathogenesis of PD and drives cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) immune regulatory pathway, contributing to neuroinflammation and dopaminergic neurodegeneration in human postmortem PD and non-PD brains as well as in experimental models of PD. We observed enhanced expression of γ-H2A.X (Ser139) a biomarker of DDSB, and decreased levels of DNA repair proteins in the brains of human PD compared to non-PD brains. This was positively correlated with upregulation of STING immune response pathways, microglial activation, senescence and dopaminergic neurodegeneration. Similarly, we observed increased and sustained DDSB as assessed by γ-H2A.X (Ser139) immunoreactivity, and degeneration of tyrosine hydroxylase-positive neurons in primary neuron/glia cultures and mice treated with 1-methyl-4-phenylpyridine (MPP+) or 1,2,3,6-tetrahydropyridine (MPTP). Next, we employed a mouse model of α-synucleinopathy, which exhibited elevated DDSBs alongside overactivation of the DNA-sensing cGAS-STING pathway and type-I interferon signaling, in association with dopaminergic neurodegeneration. Interestingly, pharmacological and genetic ablation of STING reduces DDSB, limits inflammatory response, improves behavioral function and attenuates the loss of dopaminergic neurons in this model. Our findings suggest that the accumulation of DDSBs and/or dysregulation in DNA repair proteins activate cGAS-STING mediated immune responses in the brain, potentially exacerbating dopaminergic neurodegeneration in PD. Furthermore, regulating these processes is essential for alleviating the pathological effects of PD and may offer potential therapeutic strategies.
    Keywords:  DNA damage response; Dopaminergic neurons; Parkinson’s disease; Tyrosine hydroxylase; immune response; α-Synuclein
    DOI:  https://doi.org/10.1016/j.bbi.2025.106065
  8. J Biochem Mol Toxicol. 2025 Aug;39(8): e70422
      Lower limb ischemia in diabetic patients results in poor collateral circulation and a high risk of amputation. Skeletal muscle cells release exosomes that are believed to regulate angiogenesis; however, the underlying mechanisms remain unclear. This study examined the effects of exosomes derived from skeletal muscle cells on angiogenesis. Exosomes derived from human skeletal muscle cells (HSMCs) were isolated and characterized using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. The effects of these exosomes on endothelial cells were evaluated through proliferation, migration, and tube formation assays. Differential expression of miRNAs between hypoxic and normoxic exosomes was identified through sequencing, with a focus on novel_196 and its role in regulating angiogenesis. Hypoxic skeletal muscle cells-derived exosomes significantly enhanced endothelial cell proliferation, migration, migration, and tube formation while reducing apoptosis. Sequencing analysis revealed 11 differentially expressed microRNAs, with novel_196 being notably downregulated under hypoxic conditions. The overexpression of novel_196 inhibited angiogenesis by targeting the FGF2 and p-AKT pathways. The findings indicate that targeting novel_196 under hypoxic conditions may enhance angiogenesis, improve collateral circulation, and reduce the likelihood of amputation in individuals with diabetic ischemic foot.
    Keywords:  angiogenesis; collateral circulation; diabetic foot; differential expression; hypoxic skeletal muscle‐derived exosomes; miRNAs
    DOI:  https://doi.org/10.1002/jbt.70422
  9. Geroscience. 2025 Aug 06.
      Several widely used epigenetic clocks have been developed for mice and other species, but a persistent challenge remains: different mouse clocks often yield inconsistent results. To address this limitation in robustness, we present EnsembleAge, a suite of ensemble-based epigenetic clocks. Leveraging data from over 200 perturbation experiments across multiple tissues, EnsembleAge integrates predictions from multiple penalized models. Empirical evaluations demonstrate that EnsembleAge outperforms existing clocks in detecting both pro-aging and rejuvenating interventions. Furthermore, we introduce EnsembleAge HumanMouse, an extension that enables cross-species analyses, facilitating translational research between mouse models and human studies. Together, these advances underscore the potential of EnsembleAge as a robust tool for identifying and validating interventions that modulate biological aging.
    Keywords:  Aging biomarkers; Biological age; DNA methylation; EnsembleAge; Epigenetic clocks; Healthspan; Lifespan interventions; MethylGauge dataset; Mouse models; Rejuvenation; Stress response
    DOI:  https://doi.org/10.1007/s11357-025-01808-1
  10. Med Oncol. 2025 Aug 04. 42(9): 406
       BACKGROUND: Cardiac cachexia linked to lung adenocarcinoma (LCACC) is a clinically important yet under-researched issue in cardio-oncology. LCACC is caused directly by the progression of the tumor, unlike cardiotoxicity induced by therapy. We proposed that LCACC myocardium exhibits unique transcriptomic and immunometabolic profiles.
    OBJECTIVE: To thoroughly analyze the molecular alterations in the myocardium associated with LCACC and pinpoint possible regulatory genes and therapeutic targets.
    METHODS: We conducted a comprehensive bioinformatics analysis using publicly accessible myocardial RNA-seq data (n = 4 + 4) from LCACC and control mice. The analyses comprised differential gene expression (DEG), immune deconvolution using xCell, gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) networks.
    RESULTS: In LCACC, the myocardium exhibited metabolic reprogramming characterized by increased oxidative phosphorylation (OXPHOS) and protein synthesis pathways, while cell cycle and inflammatory signaling (such as NF-κB) were downregulated. The analysis of immune profiles indicated a rise in fibroblasts and megakaryocyte-erythroid progenitors, while conventional dendritic and memory B cells were reduced. Five central genes (CCL2, CDC20, MKI67, CX3CR1, CXCL1) were discovered, grouped within chemokine signaling and cell division pathways, and linked to actionable upstream transcription factors, miRNAs, and possible drugs.
    CONCLUSION: This research offers the initial comprehensive map of transcriptomic and immunometabolic changes in LCACC. These results emphasize that LCACC involves active, regulated biological processes, indicating it is not just a passive result of cachexia, and they pave the way for further mechanistic and translational studies.
    Keywords:  Cardiac cachexia; Lung adenocarcinoma; Lung cancer–associated cardiac cachexia; Molecular mechanisms; Transcriptome analysis
    DOI:  https://doi.org/10.1007/s12032-025-02933-9
  11. Sci Rep. 2025 Aug 08. 15(1): 27825
      Skeletal muscles are classified into slow-twitch muscles composed primarily of type I and IIa fibers with high oxidative metabolism, and fast-twitch muscles composed of type IIx and IIb fibers with high glycolytic metabolism. Fiber-type shifts occur during development and aging; however, the stimuli that shift these types remain unclear. We analyzed the role of mechanical stimuli in myotube formation and shift to the characteristics of each fiber type using crosslinked gelatin gels with tunable elastic moduli (10-230 kPa) and microgrooves (3-50 µm). C2C12 myotubes on 10 kPa gel increased the expression of marker genes for type I and IIa fibers (MYH7 and MYH2) and oxidative metabolism (GLUT4 and myoglobin) than those on stiffer gels. Upregulation of PGC-1α on soft gel induced a shift toward slow-twitch muscle genetic characteristics. Microgrooves (3-10 µm) enhanced myoblast differentiation and myotube orientation, without affecting the gene expressions characterizing fiber types. This study demonstrated an approach to create highly oriented slow-twitch muscle models by controlling the elasticity and microgrooves.
    DOI:  https://doi.org/10.1038/s41598-025-12744-7
  12. Sci Rep. 2025 Aug 05. 15(1): 28555
      A growing body of knowledge implicates perturbed RNA homeostasis in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that currently has no cure and few available treatments. Dysregulation of the multifunctional RNA-binding protein TDP-43 is increasingly regarded as a convergent feature of this disease, evidenced at the neuropathological level by the detection of TDP-43 pathology in most patient tissues, and at the genetic level by the identification of disease-associated mutations in its coding gene TARDBP. To characterize the transcriptional landscape induced by TARDBP mutations, we performed whole-transcriptome profiling of motor neurons (MNs) differentiated from two knock-in iPSC lines expressing the ALS-linked TDP-43 variants p.A382T or p.G348C. Our results show that the TARDBP mutations significantly altered the expression profiles of mRNAs and microRNAs of the 14q32 cluster in MNs. Using mutation-induced gene signatures and the Connectivity Map database, we identified compounds predicted to restore gene expression toward wild-type levels. Among top-scoring compounds selected for further investigation, the NEDD8-activating enzyme inhibitor MLN4924 effectively improved cell viability and neuronal activity, highlighting a possible role for protein post-translational modification via NEDDylation in the pathobiology of TDP-43 in ALS.
    DOI:  https://doi.org/10.1038/s41598-025-12147-8