bims-musmir Biomed News
on microRNAs in muscle
Issue of 2025–04–13
eight papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. Complement pathway activation mediates pancreatic cancer-induced muscle wasting and pathological remodeling.
  2. Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture.
  3. Mitochondrial damage is associated with an early immune response in inclusion body myositis.
  4. Revisiting insulin-stimulated hydrogen peroxide dynamics reveals a cytosolic reductive shift in skeletal muscle.
  5. microRNA-133a as an indicator of disease progression and treatment response in X-linked myotubular myopathy.
  6. Constitutively Active mTORC1 Signaling Modifies the Skeletal Muscle Metabolome and Lipidome Response to Exercise.
  7. Conjugation to a transferrin receptor 1-binding Bicycle peptide enhances ASO and siRNA potency in skeletal and cardiac muscles.
  8. STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.
  1. J Clin Invest. 2025 Apr 08. pii: e178806. [Epub ahead of print]
    Complement pathway activation mediates pancreatic cancer-induced muscle wasting and pathological remodeling.
    Andrew C D'Lugos, Jeremy B Ducharme, Chandler S Callaway, Jose G Trevino, Carl Atkinson, Sarah M Judge, Andrew R Judge.
      Cancer cachexia is a multifactorial condition characterized by skeletal muscle wasting that impairs quality of life and longevity for many cancer patients. A greater understanding of the molecular etiology of this condition is needed for effective therapies to be developed. We performed a quantitative proteomic analysis of skeletal muscle from cachectic pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer controls, followed by immunohistochemical analyses of muscle cross-sections. These data provide evidence of a local inflammatory response in muscles of cachectic PDAC patients, including an accumulation of plasma proteins and recruitment of immune cells into muscle that may promote the pathological remodeling of muscle. Our data further support the complement system as a potential mediator of these processes, which we tested by injecting murine pancreatic cancer cells into wild type (WT) mice, or mice with genetic deletion of the central complement component 3 (C3-/- mice). Compared to WT mice, C3-/- mice showed attenuated tumor-induced muscle wasting and dysfunction and reduced immune cell recruitment and fibrotic remodeling of muscle. These studies demonstrate that complement activation is contributory to the skeletal muscle pathology and dysfunction in PDAC, suggesting that the complement system may possess therapeutic potential in preserving skeletal muscle mass and function.
    Keywords:  Cancer; Muscle; Muscle biology; Oncology; Proteomics
    DOI:  https://doi.org/10.1172/JCI178806
  2. EMBO Mol Med. 2025 Apr 09.
    Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture.
    Pavel A Nash, Keira M Turner, Christopher A Powell, Lindsey Van Haute, Pedro Silva-Pinheiro, Felix Bubeck, Ellen Wiedtke, Eloïse Marques, Dylan G Ryan, Dirk Grimm, Payam A Gammage, Michal Minczuk.
      Mutations in the mitochondrial genome (mtDNA) often lead to clinical pathologies. Mitochondrially-targeted zinc finger nucleases (mtZFNs) have been successful in reducing the levels of mutation-bearing mtDNA both in vivo and in vitro, resulting in a shift in the genetic makeup of affected mitochondria and subsequently to phenotypic rescue. Given the uneven distribution in the mtDNA mutation load across tissues in patients, and a great diversity in pathogenic mutations, it is of interest to develop mutation-specific, selective gene therapies that could be delivered to particular tissues. This study demonstrates the effectiveness of in vivo mitochondrial gene therapy using a novel mtZFN architecture on skeletal muscle using adeno-associated viral (AAV) platforms in a murine model harboring a pathogenic mtDNA mutation. We observed effective reduction in mutation load of cardiac and skeletal muscle, which was accompanied by molecular phenotypic rescue. The gene therapy treatment was shown to be safe when markers of immunity and inflammation were assessed. These results highlight the potential of curative approaches for mitochondrial diseases, paving the way for targeted and effective treatments.
    Keywords:  Adeno-Associated Viruses (AAV); Gene Therapy; Skeletal Muscle; Zinc Finger Nuclease (mtZFN); mtDNA Heteroplasmy Modification
    DOI:  https://doi.org/10.1038/s44321-025-00231-5
  3. Brain. 2025 Apr 07. pii: awaf118. [Epub ahead of print]
    Mitochondrial damage is associated with an early immune response in inclusion body myositis.
    Felix Kleefeld, Emily Cross, Daniel Lagos, Sara Walli, Benedikt Schoser, Andreas Hentschel, Tobias Ruck, Christopher Nelke, Katrin Hahn, Denisa Hathazi, Andrew L Mammen, Maria Casal-Dominguez, Marta Gut, Ivo Glynne Gut, Simon Heath, Anne Schänzer, Hans-Hilmar Goebel, Iago Pinal-Fernandez, Andreas Roos, Corinna Preuße, Werner Stenzel, Rita Horvath.
      Polymyositis with mitochondrial pathology (PM-Mito) was first identified in 1997 as a subtype of idiopathic inflammatory myopathy. Recent findings demonstrated significant molecular similarities between PM-Mito and Inclusion Body Myositis (IBM), suggesting a trajectory from early to late IBM and prompting the inclusion of PM-Mito as an IBM precursor (early IBM) within the IBM spectrum. Both PM-Mito and IBM show mitochondrial abnormalities, suggesting mitochondrial disturbance is a critical element of IBM pathogenesis. The primary objective of this cross-sectional study was to characterize the mitochondrial phenotype in PM-Mito at histological, ultrastructural, and molecular levels and to study the interplay between mitochondrial dysfunction and inflammation. Skeletal muscle biopsies of 27 patients with PM-Mito and 27 with typical IBM were included for morphological and ultrastructural analysis. Mitochondrial DNA (mtDNA) copy number and deletions were assessed by qPCR and long-range PCR, respectively. In addition, full-length single-molecule sequencing of the mtDNA enabled precise mapping of deletions. Protein and RNA levels were studied using unbiased proteomic profiling, immunoblotting, and bulk RNA sequencing. Cell-free mtDNA (cf-mtDNA) was measured in the serum of IBM patients. We found widespread mitochondrial abnormalities in both PM-Mito and IBM, illustrated by elevated numbers of COX-negative and SDH-positive fibers and prominent ultrastructural abnormalities with disorganized and concentric cristae within enlarged and dysmorphic mitochondria. MtDNA copy numbers were significantly reduced, and multiple large-scale mtDNA deletions were already evident in PM-Mito, compared to healthy age-matched controls, similar to the IBM group. The canonical cGAS/STING inflammatory pathway was activated in PM-Mito and IBM, and we detected elevated levels of circulating cf-mtDNA indicative of mtDNA leakage. In PM-Mito and IBM, these findings were accompanied by dysregulation of proteins and transcripts linked to the mitochondrial membranes. In summary, we identified that mitochondrial dysfunction with multiple mtDNA deletions and depletion, disturbed mitochondrial ultrastructure, and defects of the inner mitochondrial membrane are features of PM-Mito and IBM, underlining the concept of an IBM-spectrum disease (IBM-SD). Notably, mitochondrial abnormalities precede tissue remodeling and infiltration by specific T-cell subpopulations (e.g., KLRG1+) characteristic of late IBM. The activation of inflammatory, DNA-sensing pathways might be related to mtDNA release, which would indicate a significant role of mitochondria-associated inflammation in the pathogenesis of IBM-SD. This study highlights the critical role of early mitochondrial abnormalities in the pathomechanism of IBM, which may lead to new approaches to therapy.
    Keywords:  IBM-SD; PM-Mito; mitochondria; polymyositis with mitochondrial pathology
    DOI:  https://doi.org/10.1093/brain/awaf118
  4. Redox Biol. 2025 Mar 25. pii: S2213-2317(25)00120-X. [Epub ahead of print]82 103607
    Revisiting insulin-stimulated hydrogen peroxide dynamics reveals a cytosolic reductive shift in skeletal muscle.
    Carlos Henríquez-Olguín, Samantha Gallero, Anita Reddy, Kaspar W Persson, Farina L Schlabs, Christian T Voldstedlund, Gintare Valentinaviciute, Roberto Meneses-Valdés, Casper M Sigvardsen, Bente Kiens, Edward T Chouchani, Erik A Richter, Thomas E Jensen.
      The intracellular redox state is crucial for insulin responses in peripheral tissues. Despite the longstanding belief that insulin signaling increases hydrogen peroxide (H2O2) production leading to reversible oxidation of cysteine thiols, evidence is inconsistent and rarely involves human tissues. In this study, we systematically investigated insulin-dependent changes in subcellular H2O2 levels and reversible cysteine modifications across mouse and human skeletal muscle models. Utilizing advanced redox tools-including genetically encoded H2O2 sensors and non-reducing immunoblotting-we consistently observed no increase in subcellular H2O2 levels following insulin stimulation. Instead, stoichiometric cysteine proteome analyses revealed a selective pro-reductive shift in cysteine modifications affecting insulin transduction related proteins, including Cys179 on GSK3β and Cys416 on Ras and Rab Interactor 2 (RIN2). Our findings challenge the prevailing notion that insulin promotes H2O2 generation in skeletal muscle and suggest that an insulin-stimulated pro-reductive shift modulates certain aspects of insulin signal transduction.
    DOI:  https://doi.org/10.1016/j.redox.2025.103607
  5. Mol Ther Nucleic Acids. 2025 Jun 10. 36(2): 102507
    microRNA-133a as an indicator of disease progression and treatment response in X-linked myotubular myopathy.
    Nika Maani, Dakota Gustafson, Peter MacDonald, Emanuela Pannia, Crizza Ching, Nesrin Sabha, Jason E Fish, Matthew S Alexander, James J Dowling.
      X-linked myotubular myopathy (XLMTM) is a rare pediatric neuromuscular disease caused by loss-of-function variants in myotubularin (MTM1). With novel therapies entering clinical trials, the discovery of robust biomarkers that reflect disease severity and therapeutic efficacy is critically required. Using high-throughput and directed approaches, we identified a decrease in miR-133a expression as a marker of XLMTM disease in skeletal muscle and plasma of a mouse model of XLMTM (Mtm1 KO). miR-133a is a muscle-enriched non-coding RNA (myomiR) involved in muscle development and function and is implicated in the regulation of the XLMTM modifier gene DNM2. miR-133a has emerged as both a treatment-effect biomarker and therapeutic candidate in other neuromuscular diseases. We demonstrate that miR-133a expression negatively correlates with disease severity in Mtm1 KO mice and is upregulated in response to treatments that improve DNM2 expression and/or significantly rescue XLMTM. Moreover, we show that miR-133a expression in treated Mtm1 KO mice positively correlates with treatment response and was shown to have high discrimination accuracy for XLMTM by linear discriminant analysis (79%-90%) and receiver operating characteristic curve analysis (AUC >0.80). These results support miR-133a as a robust, circulating biomarker that reflects disease severity and treatment response in XLMTM.
    Keywords:  MT: Non-coding RNAs; biomarker; microRNA; muscle disease; myotubular myopathy; therapy
    DOI:  https://doi.org/10.1016/j.omtn.2025.102507
  6. J Appl Physiol (1985). 2025 Apr 11.
    Constitutively Active mTORC1 Signaling Modifies the Skeletal Muscle Metabolome and Lipidome Response to Exercise.
    Hanna Kalenta, Sean P Kilroe, Trevor B Romsdahl, Erik D Marchant, Rosario Maroto, Jennifer J Linares, William K Russell, Blake B Rasmussen.
      A chronic increase in mTORC1 signaling is implicated in reduced longevity, altered metabolism, and mitochondrial dysfunction. Abnormal mTORC1 signaling may also be involved in the etiology of sarcopenia. To better understand the role of mTORC1 signaling in the regulation of muscle metabolism we developed an inducible muscle specific DEPDC5 knockout model which results in constitutively active mTORC1 signaling. We hypothesized that constitutively active mTORC1 signaling in skeletal muscle would alter the metabolomic and lipidomic response to an acute bout of exercise. Wild-type (WT) and DEPDC5 muscle specific knockout (KO) mice were studied at rest and following a 1 hr bout of treadmill exercise. Acute exercise induced an increased reliance on glycolytic and PPP metabolites in the muscle of mice with hyperactive mTORC1. Lipidomic analysis showed an increase in triacylglycerols (TGs) in KO mice. While exercise had a pronounced effect on muscle metabolism, the genotype effect was larger, indicating that constitutively active mTORC1 signaling exerts a dominant influence on metabolic and lipidomic regulation. We conclude that increased mTORC1 signaling shifts muscle metabolism toward greater reliance on non-oxidative energy sources in response to exercise. Understanding the mechanisms responsible for these effects may lead to the development of strategies for restoring proper mTORC1 signaling in conditions such as aging and sarcopenia.
    Keywords:  Metabolomics; exercise; lipidomics; mTORC1; muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00987.2024
  7. Nucleic Acids Res. 2025 Apr 10. pii: gkaf270. [Epub ahead of print]53(7):
    Conjugation to a transferrin receptor 1-binding Bicycle peptide enhances ASO and siRNA potency in skeletal and cardiac muscles.
    Michael E Østergaard, Michele Carrer, Brooke A Anderson, Megan Afetian, Mohsen A Bakooshli, Jinro A Santos, Stephanie K Klein, Juliana Capitanio, Graeme C Freestone, Michael Tanowitz, Rodrigo Galindo-Murillo, Hans J Gaus, Chrissa A Dwyer, Michaela Jackson, Paymaan Jafar-Nejad, Frank Rigo, Punit P Seth, Katherine U Gaynor, Steven J Stanway, Liudvikas Urbonas, Megan A St Denis, Simone Pellegrino, Gustavo A Bezerra, Michael Rigby, Ellen Gowans, Katerine Van Rietschoten, Paul Beswick, Liuhong Chen, Michael J Skynner, Eric E Swayze.
      Improving the delivery of antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) to skeletal and cardiac muscles remains a pivotal task toward the broader application of oligonucleotide therapeutics. The targeting of myofibers and cardiomyocytes via conjugation of ASOs and siRNAs to ligands that bind the human transferrin receptor 1 (TfR1) has gathered significant interest in recent years. However, the selection of ligands with low molecular weight and optimal biophysical and binding properties is crucial to maximize the potential of the TfR1 ligand-conjugated antisense (LICA) technology. Here, through effective combination of phage display and peptide medicinal chemistry, we identified and characterized a bicyclic peptide (Bicycle® molecule BCY17901), with a molecular weight of ∼2 kDa, that binds human TfR1 with high affinity and specificity. Conjugation to BCY17901 improved ASO and siRNA potency in skeletal and cardiac muscles of human TfR1 knock-in mice, after either intravenous or subcutaneous administration. Furthermore, single-nucleus RNA sequencing showed that conjugation to BCY17901 enhanced ASO activity in myonuclei of different muscle fiber types. Importantly, we demonstrated good translatability of our TfR1-targeting platform in skeletal and cardiac muscles of nonhuman primates. Our results offer great promise toward potential future applications of low-molecular-weight Bicycle LICA therapeutics for the treatment of diseases affecting skeletal muscle and heart.
    DOI:  https://doi.org/10.1093/nar/gkaf270
  8. Mol Cell. 2025 Mar 27. pii: S1097-2765(25)00201-1. [Epub ahead of print]
    STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.
    Zhen Tang, Cong Xing, Antonina Araszkiewicz, Kun Yang, Wanwan Huai, Devon Jeltema, Nicole Dobbs, Yihe Zhang, Lu O Sun, Nan Yan.
      Lysosomes are essential organelles for cellular homeostasis. Defective lysosomes are associated with diseases like lysosomal storage disorders (LSDs). How lysosomal defects are detected and lysosomal function restored remain incompletely understood. Here, we show that STING mediates a neuroinflammatory gene signature in three distinct LSD mouse models, Galctwi/twi, Ppt1-/-, and Cln7-/-. Transcriptomic analysis of Galctwi/twi mouse brain tissue revealed that STING also mediates the expression of lysosomal genes that are regulated by transcriptional factor EB (TFEB). Immunohistochemical and single-nucleus RNA-sequencing (snRNA-seq) analysis show that STING regulates lysosomal gene expression in microglia. Mechanistically, we show that STING activation leads to TFEB dephosphorylation, nuclear translocation, and expression of lysosomal genes. This process requires STING's proton channel function, the V-ATPase-ATG5-ATG8 cascade, and is independent of immune signaling. Furthermore, we show that the STING-TFEB axis facilitates lysosomal repair. Together, our data identify STING-TFEB as a lysosomal quality control mechanism that responds to lysosomal dysfunction.
    Keywords:  Krabbe disease; Niemann-Pick disease; STING; TFEB; innate immunity; lysosomal storage disorder; lysosome repair; neuroinflammation; non-canonical autophagy
    DOI:  https://doi.org/10.1016/j.molcel.2025.03.008
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