bims-musmir Biomed News
on microRNAs in muscle
Issue of 2025–12–28
eight papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. Decoding muscle-resident Schwann cell dynamics during neuromuscular junction remodeling.
  2. Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.
  3. Mitochondrial proteostasis regulated by CRL5Ozz and Alix modulates skeletal muscle metabolism and fiber type.
  4. Single-Nuclei Resolution of Intermuscular Adipose Tissue Indicates an Inflammation-Associated Cellular Profile in Individuals With Knee Osteoarthritis: Findings From the SOMMA KOA Ancillary Study.
  5. Transient muscle expression of mitoARCUS in mice leads to a sustained reduction in pathogenic mtDNA content and improves muscle function.
  6. Mitochondrial DNA release via mPTP and BAX/BAK drives inflammatory injury in intestinal ischemia reperfusion.
  7. Lysosomal swelling triggers LRRK2 activity.
  8. Mitochondrial DNA copy number reduction via in vitro TFAM knockout remodels the nuclear epigenome and transcriptome.
  1. JCI Insight. 2025 Dec 23. pii: e195917. [Epub ahead of print]
    Decoding muscle-resident Schwann cell dynamics during neuromuscular junction remodeling.
    Steve D Guzman, Ahmad Abu-Mahfouz, Carol S Davis, Lloyd P Ruiz, Peter Cd Macpherson, Susan V Brooks.
      This investigation leverages single-cell RNA sequencing (scRNA-Seq) to delineate the contributions of muscle-resident Schwann cells to neuromuscular junction (NMJ) remodeling by comparing a model of stable innervation with models of reinnervation following partial or complete denervation. The study discovered multiple distinct Schwann cell subtypes, including a novel terminal Schwann cell (tSC) subtype integral to the denervation-reinnervation cycle, identified by a transcriptomic signature indicative of cell migration and polarization. The data also characterizes three myelin Schwann cell subtypes, which are distinguished based on enrichment of genes associated with myelin production, mesenchymal differentiation or collagen synthesis. Importantly, SPP1 signaling emerges as a pivotal regulator of NMJ dynamics, promoting Schwann cell proliferation and muscle reinnervation across nerve injury models. These findings advance our understanding of NMJ maintenance and regeneration and underscore the therapeutic potential of targeting specific molecular pathways to treat neuromuscular and neurodegenerative disorders.
    Keywords:  Cell biology; Muscle biology; Skeletal muscle; Synapses; Transcriptomics
    DOI:  https://doi.org/10.1172/jci.insight.195917
  2. Autophagy. 2025 Dec 26.
    Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis.
    Ang Li, Shu-Qin Cao, Evandro F Fang, Huanxing Su.
      Mitochondrial dysfunction is widely recognized as a key driver of aging and neurodegenerative diseases, with mitophagy acting as an essential cellular mechanism for the selective clearance of damaged mitochondria. While pharmacological activation of mitophagy has been reported to exert beneficial effects across multiple neurodegenerative diseases, its functional relevance in amyotrophic lateral sclerosis (ALS) remains poorly characterized. Our recent study published in EMBO Molecular Medicine demonstrates that PINK1-PRKN-dependent mitophagy is markedly impaired in ALS motor neurons. Through high-content drug screening, we identified a potent mitophagy agonist isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba that stabilizes the PINK1-TOMM complex on the outer mitochondrial membrane, enhances PINK1-PRKN-dependent mitophagy, and ameliorates motor neuron degeneration in ALS-like Caenorhabditis elegans, mouse models, and induced pluripotent stem cell-derived motor neurons. Consequently, ISO is able to alleviate ALS-associated phenotypes. In this commentary, we contextualize these findings broadly to discuss whether pharmacologically induced mitophagy can act as an effective therapeutic strategy, distinct from current clinical approaches, for the development of ALS-targeted treatments.
    Keywords:  ALS; PINK1-Parkin; isoginkgetin; mitophagy; motor neurons
    DOI:  https://doi.org/10.1080/15548627.2025.2610450
  3. Commun Biol. 2025 Dec 22.
    Mitochondrial proteostasis regulated by CRL5Ozz and Alix modulates skeletal muscle metabolism and fiber type.
    Yvan Campos, Gustavo Palacios, Elida Gomero, Diantha van de Vlekkert, Krishnan Venkataraman, Jaison John, Jason Andrew Weesner, Randall Wakefield, Xiaohui Qiu, Ricardo Rodriguez-Enriquez, Stephanie Rockfield, Jeroen Demmers, Joseph T Opferman, Cam Robinson, Khaled Khairy, Tulio Bertorini, Gerard C Grosveld, Alessandra d'Azzo.
      High-energy-demanding tissues, such as skeletal muscle, rely on mitochondrial proteostasis for proper function. Two key quality-control mechanisms -the ubiquitin proteasome system (UPS) and the release of mitochondria-derived vesicles- help maintain mitochondrial proteostasis, but whether these processes interact remains unclear. Here, we show that CRL5Ozz and its substrate, Alix, localize to mitochondria and together regulate the levels and distribution of the mitochondrial solute carrier Slc25A4, which is essential for ATP production. In Ozz-/- or Alix-/- mice, skeletal muscle mitochondria exhibit similar morphological abnormalities, including swelling and dysmorphism, along with partially overlapping metabolomic alterations. We demonstrate that CRL5Ozz ubiquitinates Slc25A4, targeting it for proteasomal degradation, while Alix facilitates Slc25A4 loading into exosomes for lysosomal degradation. Loss of Ozz or Alix in vivo disrupts the steady-state levels of Slc25A4, impairing mitochondrial metabolism and triggering a switch in muscle fiber composition from oxidative, mitochondria-rich slow to glycolytic fast fibers.
    DOI:  https://doi.org/10.1038/s42003-025-09363-3
  4. Aging Cell. 2026 Jan;25(1): e70348
    Single-Nuclei Resolution of Intermuscular Adipose Tissue Indicates an Inflammation-Associated Cellular Profile in Individuals With Knee Osteoarthritis: Findings From the SOMMA KOA Ancillary Study.
    Line O Elingaard-Larsen, Katie L Whytock, Adeline Divoux, Cheehoon Ahn, Giovanna Distefano, Bret H Goodpaster, Paul M Coen, Jamie N Justice, Erin E Kershaw, Nancy E Lane, Lauren M Sparks.
      Individuals with knee osteoarthritis (KOA) have skeletal muscle changes around the knee joint including reduced quadricep muscle mass and increased intermuscular adipose tissue (IMAT). We examined the cellular composition and transcriptional profiles using single-nuclei RNA sequencing in IMAT from 6 older women with KOA and knee pain and 5 older women without KOA or knee pain from the Study of Muscle, Mobility and Aging (SOMMA). From the resulting 21,436 nuclei, we identified 6 major cell types with unique transcriptional profiles, including progenitor cells, adipocytes, macrophages and other immune cells (T/B/NK cells), endothelial cells and smooth muscle cells/pericytes. Sub-clustering of the immune cell population revealed the presence of mast cells and B-cells with greater abundances in the KOA group. The adipocyte population was the most transcriptional diverse population between the KOA group and the group without KOA. Cell-cell communication network analysis highlighted that adipocytes had the most prominent signaling role of all cell types, independent of KOA status; however, signaling of the pro-inflammatory adipokine leptin was enriched in the KOA group. This study provides the first interrogation of the cellular diversity and transcriptional profiles of IMAT in individuals with KOA. Our findings suggest that IMAT may contribute to KOA disease burden potentially through pro-inflammatory signaling.
    Keywords:  intermuscular adipose tissue; knee osteoarthritis; single nuclei RNA‐sequencing
    DOI:  https://doi.org/10.1111/acel.70348
  5. Mol Ther. 2025 Dec 24. pii: S1525-0016(25)01064-0. [Epub ahead of print]
    Transient muscle expression of mitoARCUS in mice leads to a sustained reduction in pathogenic mtDNA content and improves muscle function.
    Sandra R Bacman, Wendy Shoop, C Spencer Henley-Beasley, Rhese Thompson, Jose Domingo Barrera-Paez, Lise-Michelle Theard, Monica Rodriguez-Silva, Cassandra Gorsuch, Elisabeth R Barton, Carlos T Moraes.
      Mitochondrial myopathies are often caused by heteroplasmic mutations in the mitochondrial DNA (mtDNA). In muscle, biochemical, pathological, and clinical impairments are observed only when the ratios of mutant/wild-type mtDNA are high. Because reductions in mutant mtDNA loads are essentially permanent, we reasoned that transient expression of a therapeutic mitochondrial nuclease could be sufficient to permanently alter heteroplasmy. We expressed a mitochondrial targeted gene editing nuclease (mitoARCUS) via intramuscular injection of lipid nanoparticle (LNP)/mRNA complexes in a mouse model of mtDNA disease (m.5024C>T in the mt-tRNAAla gene). Transient expression of mitoARCUS in the tibialis anterior (TA) led to a robust decrease in mtDNA mutation load which was maintained up to forty-two weeks after injection. A molecular marker of the mitochondrial defect in this model, namely low levels of mt-tRNAAla, were markedly improved in treated muscles. Muscle force assessment in situ after repeated stimulation showed that fatigability was improved in the treated TA. Finally, we showed that multi-muscle injections can alter mtDNA heteroplasmy essentially in whole limbs. These results demonstrate that transient expression of mitoARCUS via LNP/mRNA intramuscular injections have long-lasting positive effects in muscles afflicted with mitochondrial myopathy.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.12.041
  6. Cell Commun Signal. 2025 Dec 24.
    Mitochondrial DNA release via mPTP and BAX/BAK drives inflammatory injury in intestinal ischemia reperfusion.
    Yixin Jing, Yiguo Zhang, Tulanisa Kadier, Ke Ding, Rong Chen, Qingtao Meng.
       BACKGROUND: Intestinal ischemia reperfusion (IIR) is a challenging and life-threatening clinical condition, with disease progression closely linked to excessive inflammatory responses. As a potent activator of innate immunity, the mechanism underlying mitochondrial DNA (mtDNA) release across the mitochondrial membrane remains incompletely elucidated.
    METHODS: In this study, an in vivo IIR model was established by clamping the superior mesenteric artery in male mice, and an in vitro hypoxia reoxygenation (HR) model was constructed using Caco-2 cells. Combining multiple techniques including RNA sequencing, subcellular organelle isolation, laser confocal imaging, siRNA transfection, protein cross-linking, Western blotting, enzyme-linked immunosorbent assay (ELISA), and quantitative real-time PCR (qPCR), the regulatory mechanisms of mtDNA release and its biological effects in IIR were systematically verified.
    RESULTS: We found that IIR significantly induced an increase in cytosolic and circulating mtDNA levels, correlating with inflammatory cytokine production. Mechanistic studies revealed that calcium overload mediated by the mitochondrial calcium uniporter (MCU) triggered the opening of the mitochondrial permeability transition pore (mPTP). Meanwhile, the pro-apoptotic protein BAX was recruited to mitochondria and interacted with BAK to form outer mitochondrial membrane oligomeric pores. Notably, although mPTP opening was independent of the BAX/BAK pathway, the two pathways exhibited sequential synergistic effects during mtDNA release. Inhibition of either pathway significantly reduced mtDNA release, decreased inflammatory cytokine levels, and alleviated intestinal tissue injury caused by IIR.
    CONCLUSIONS: These findings identify mtDNA as a potential biomarker for IIR and highlight the MCU-mPTP-BAX/BAK axis as a therapeutic target.
    Keywords:  BAX/BAK; IIR; MCU; mPTP; mtDNA
    DOI:  https://doi.org/10.1186/s12964-025-02603-3
  7. bioRxiv. 2025 Dec 12. pii: 2025.12.09.693280. [Epub ahead of print]
    Lysosomal swelling triggers LRRK2 activity.
    Tuyana Malankhanova, Zhiyong Liu, Samuel Strader, Weiping Wang, Kiwoon Sung, Zhong Li, Shawn M Ferguson, Andrew B West.
      LRRK2 is implicated in lysosomal functions, but the physiological upstream cues that engage endogenous LRRK2 activity are incompletely defined. Here we show that lysosomal swelling serves as a selective and reversible trigger for LRRK2-mediated Rab phosphorylation, without requiring membrane damage. Acute inhibition of PIKfyve, but not the general disruption of phosphoinositide signaling, induces the robust accumulation of phosphorylated Rabs across endolysosomal membranes. Rescue of swelling through pharmacological restoration of lysosomal ionic imbalances from PIKfyve inhibition suppresses LRRK2 activation without restoring lysosomal function. Mechanical lysosomal swelling from indigestible osmolyte uptake causes a dose-dependent increase in LRRK2-mediated Rab phosphorylation on both swollen and non-swollen lysosomes. Together, these findings identify LRRK2 as a sensor of lysosomal volume and mechanical stress, not specifically membrane damage or PIKfyve inhibition. As lysosomal swelling is a shared pathological feature across LRRK2 -linked diseases, these results reframe LRRK2 as part of an endolysosomal surveillance system responsive to lysosomal distension.
    DOI:  https://doi.org/10.64898/2025.12.09.693280
  8. Epigenomics. 2025 Dec 23. 1-18
    Mitochondrial DNA copy number reduction via in vitro TFAM knockout remodels the nuclear epigenome and transcriptome.
    Phyo W Win, Julia Nguyen, Elly H Shin, Tyler S Nagano, Brent Selimi, Katie Hong, Anahita M Meybodi, Bradley P Yates, Emma V Burke, David E Carter, Gregory A Newby, Charles Newcomb, Dan E Arking, Christina A Castellani.
       AIMS: Mitochondrial DNA copy number (mtDNA-CN) is associated with several age-related chronic diseases and is a predictor of all-cause mortality. Here, we examine site-specific differential nuclear DNA (nDNA) methylation and differential gene expression resulting from in vitro reduction of mtDNA-CN to uncover shared genes and biological pathways mediating the effect of mtDNA-CN on disease.
    MATERIALS AND METHODS: Epigenome and transcriptome profiles were generated for three independent human embryonic kidney (HEK293T) cell lines harboring a mitochondrial transcription factor A (TFAM) knockout generated via CRISPR-Cas9, and matched control lines.
    RESULTS: We identified 2924 differentially methylated sites, 67 differentially methylated regions, and 102 differentially expressed genes associated with mtDNA-CN. Integrated analysis uncovered 24 Gene-CpG pairs. GABAA receptor genes and related pathways, the neuroactive ligand signaling pathway, ABCD1/2 gene activity, and cell signaling processes were overrepresented, providing insight into the underlying biological mechanisms facilitating these associations. We also report evidence implicating chromatin state regulatory mechanisms as modulators of mtDNA-CN effect on gene expression.
    CONCLUSIONS: We demonstrate that mitochondrial DNA variation signals to the nuclear DNA epigenome and transcriptome and may lead to nuclear remodeling relevant to development, aging, and complex disease.
    Keywords:  Mitochondria; epigenome; mitochondrial DNA; mitochondrial DNA copy number; transcriptome
    DOI:  https://doi.org/10.1080/17501911.2025.2603883
This page is being maintained by Thomas Krichel. It was last updated on 2025‒12‒30 at 20:03.