bims-musmir Biomed News
on microRNAs in muscle
Issue of 2026–07–12
ten papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. BCAAs, LAT1, and the Metabolic Competition between Tumor and Peripheral Tissues during Cancer Cachexia.
  2. C9orf72-associated poly-GR in skeletal muscle leads to neuromuscular junction deficits and muscle atrophy.
  3. Neuromuscular junction failure in sarcopenia is linked to NaV1.4 loss and reversed by ClC-1 inhibition.
  4. Transcriptomic Evidence of Mitochondrial Double-Stranded RNA Accumulation in Brain Aging and Alzheimer's Disease.
  5. Pik3ip1 mediates thyroid hormone-dependent regulation of the PI3K/Akt/mTOR axis in muscle atrophy.
  6. Exercise-associated microbial metabolites prevent skeletal muscle atrophy in adult female mice.
  7. Electroacupuncture ameliorates disuse muscular atrophy and inhibits the NLRP3 inflammasome and SIRT1 through miR-133a in a mouse model.
  8. Mitochondrial transcription factor A: linking mtDNA maintenance, mitochondrial stress responses, and inflammaging.
  9. Trans-species microRNAs from the parasitic plant Cuscuta campestris specifically avoid loading onto self Argonautes.
  10. Intestinal lipid metabolism controls immune response through NHR-68 and gut-brain signaling in C. elegans.
  1. Am J Physiol Regul Integr Comp Physiol. 2026 Jul 09.
    BCAAs, LAT1, and the Metabolic Competition between Tumor and Peripheral Tissues during Cancer Cachexia.
    Jessica L Halle, Benjamin F Miller.
      
    Keywords:  BCAA; Cancer Cachexia; Colorectal Cancer; LAT1; Metabolism
    DOI:  https://doi.org/10.1152/ajpregu.00219.2026
  2. Mol Ther. 2026 Jul 09. pii: S1525-0016(26)00567-8. [Epub ahead of print]
    C9orf72-associated poly-GR in skeletal muscle leads to neuromuscular junction deficits and muscle atrophy.
    Xinyi Tan, Shuangshuang Sun, Yuqing Yan, Wei Li, Ning Ding, Lin Xu, Liying He, Yuhao Zhang, Wenbing Chen, Yongjun Zheng, Lei Li.
      Hexanucleotide repeat expansions in C9orf72 produce dipeptide repeat (DPR) proteins that are widely expressed, including the nervous system and skeletal muscle. Among these DPRs, arginine-containing proteins, poly-GR and poly-PR are toxic in the nervous system, but whether DPRs in skeletal muscle contribute to ALS pathogenesis is unclear. Here, we show that muscle-restricted expression of poly-GR drives motor deficits in mice, including muscle atrophy and neuromuscular junction (NMJ) deficits. Poly-GR in muscle interacted with the NMJ key organizer MuSK and promoted MuSK degradation, disrupting postsynaptic structure and impairing neuromuscular transmission. Importantly, a MuSK agonist antibody (X-17) stabilized NMJs and rescued neuromuscular transmission. Moreover, poly-GR in muscle activated the integrated stress response (ISR), elevating eIF2α phosphorylation and broadly suppressing protein translation. ISR inhibition with ISRIB restored translation and MuSK protein levels, and ameliorated both muscle atrophy and NMJ deficits. These findings demonstrate that skeletal muscle actively contributes to C9orf72-ALS pathology. Targeting muscle with ISRIB offers a therapeutic strategy to preserve motor function in C9orf72-ALS.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.07.002
  3. J Clin Invest. 2026 Jul 09. pii: e190646. [Epub ahead of print]
    Neuromuscular junction failure in sarcopenia is linked to NaV1.4 loss and reversed by ClC-1 inhibition.
    W David Arnold, Jeanette Jeppesen Morgen, Pernille Bogetofte Thomasen, Martin Broch-Lips, Leatha A Clark, Thomas Groennebaek, Martin Skov, Jeppe Blichfeldt Winther, Abdullah F Ramadan, Philippa A Rust, Jessica H Myers, Fereshteh B Darvishi, Anna R Dashtmian, Lauren A Fish, Deepti Chugh, Jane Bold, Jorge A Quiroz, John Hutchison, Hiroshi Nishimune, Ross A Jones, Xueyong Wang, Justin R Fallon, Thomas H Gillingwater, Mark M Rich, Thomas Holm Pedersen, Brian C Clark.
      Sarcopenia is the age-related loss of muscle strength and size that leads to mobility limitations and loss of independence in older adults. The underlying cellular mechanisms remain unclear, and treatments are limited. As the critical interface between the nervous system and muscle, the neuromuscular junction (NMJ) is essential for muscle activation and force production. Here, we demonstrate that weak older individuals exhibit NMJ transmission failure that correlates with muscle weakness severity. Preclinical experiments showed similar NMJ transmission failure in aged rodents that was associated with localized loss of muscle fiber excitability at the NMJ. This excitability defect, distinct from potential synaptic cholinergic transmission abnormalities, represents a novel disease mechanism of sarcopenia. Across species, immunohistochemistry identified a localized reduction in the voltage-gated sodium channel specific for skeletal muscle (NaV1.4) at the post-synaptic NMJ membrane. Acute NaV1.4 inhibition with μ-conotoxin GIIIB in adult rats reproduced findings of NMJ transmission failure observed in aged rodents and humans. Finally, ClC-1 chloride ion channel inhibition enhanced muscle excitability and improved NMJ transmission and muscle function in old rodents. Together, these findings demonstrate that NMJ transmission deficits are a key, reversible driver of sarcopenia and reveal a novel therapeutic target for addressing muscle weakness in aging.
    Keywords:  Aging; Excitation contraction coupling; Neuroscience; Sodium channels; Synapses
    DOI:  https://doi.org/10.1172/JCI190646
  4. Aging Cell. 2026 Jul;25(7): e70616
    Transcriptomic Evidence of Mitochondrial Double-Stranded RNA Accumulation in Brain Aging and Alzheimer's Disease.
    Rachel L Doser, Thomas J LaRocca.
      Mitochondria and inflammation are tightly linked in aging and Alzheimer's disease (AD), and recent evidence implicates mitochondrial double-stranded RNA (mt-dsRNA) as a potential trigger of inflammation. We examined mt-dsRNA accumulation and dsRNA signaling in brain aging and AD using complementary human brain tissue and in vitro transcriptomic datasets by quantifying mitochondrial transcripts, dsRNA editing, and related gene expression patterns. We found that mt-dsRNA signatures increased after midlife and coincided with reduced expression of mitochondrial RNA processing and translation machinery, along with increased expression of dsRNA antiviral signaling proteins, consistent with cytoplasmic mt-dsRNA-driven inflammation. In AD brains, mt-dsRNA signatures were further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin-dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt-dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age- and AD-related neurodegeneration and identify mt-dsRNA as a potential driver of chronic inflammation in the brain.
    Keywords:  Alzheimer's disease; aging; brain; double‐stranded RNA; inflammation; mitochondrial RNA
    DOI:  https://doi.org/10.1111/acel.70616
  5. Mol Metab. 2026 Jul 06. pii: S2212-8778(26)00097-9. [Epub ahead of print] 102413
    Pik3ip1 mediates thyroid hormone-dependent regulation of the PI3K/Akt/mTOR axis in muscle atrophy.
    Annarita Nappi, Serena Sagliocchi, Federica Restolfer, Caterina Miro, Lucia Acampora, Giovanna Giuseppina Altobelli, Monica Dentice, Annunziata Gaetana Cicatiello.
      Skeletal muscle atrophy is driven by an imbalance between anabolic and catabolic signaling pathways, often involving suppression of the PI3K/Akt/mTOR axis. Thyroid Hormones (THs) are key endocrine regulators of skeletal muscle metabolism and adaptation, exerting context-dependent effects that promote either muscle atrophy or hypertrophy. Here, we identify Phosphoinositide-3-kinase interacting protein 1, Pik3ip1, as a critical regulator of TH-dependent muscle homeostasis. Transcriptomic profiling of skeletal muscle from muscle-specific D2 knockout (mD2KO) and TH Receptor knockout (TRKO) mice revealed a catabolic transcriptional program associated with increased Pik3ip1 expression. Consistently, Pik3ip1 expression negatively correlated with TH signaling in vivo and in vitro. Functional studies in C2C12 myotubes showed that Pik3ip1 overexpression suppresses Akt/mTOR signaling, indicating that its induction is sufficient to impair anabolic pathway activation. In vivo, Pik3ip1 expression was rapidly induced during denervation-induced muscle atrophy and remained persistently elevated in mD2KO and TRKO muscles, characterized by altered TH signaling. Sustained Pik3ip1 expression was associated with impaired activation of the Akt/mTOR pathway and enhanced muscle wasting. Conversely, TH treatment reduced Pik3ip1 levels, restored Akt/mTOR signaling, and promoted anabolic responses. Forced Pik3ip1 expression attenuated TH-induced Akt/mTOR phosphorylation, confirming its role as a mediator of TH-dependent anabolic regulation. Collectively, these findings identify Pik3ip1 as a key negative regulator of PI3K/Akt/mTOR signaling in skeletal muscle and establish the TH-Pik3ip1 axis as an important mechanism controlling muscle mass maintenance during atrophic conditions.
    Keywords:  Anabolic signaling; Denervation; Metabolic regulation; Muscle atrophy; PI3K/Akt/mTOR pathway; Skeletal muscle; Thyroid hormone
    DOI:  https://doi.org/10.1016/j.molmet.2026.102413
  6. Nat Commun. 2026 Jul 10.
    Exercise-associated microbial metabolites prevent skeletal muscle atrophy in adult female mice.
    Benjamin I Burke, Taylor R Valentino, Ahmed Ismaeel, Salim S El-Amouri, Jensen Goh, Logan N Scott, Bonnie J Walton, Jai K Joshi, Cecily R Wood, Abigail Burrows-Franco, John B May, Lance A Johnson, Michael D Flythe, Yuan Wen, John J McCarthy.
      We previously reported that skeletal muscle adaptation to regular exercise requires a healthy gut microbiome, contributing to growing evidence that some exercise benefits are mediated by microbiome-derived metabolites. Here, to identify such exercise-associated microbial metabolites, we transfer cecal contents from exercise-trained female donor mice into exercise-naïve female recipient mice undergoing unilateral hindlimb immobilization. Recipients of cecal material from exercise-trained donors exhibit less muscle atrophy compared with those receiving transfers from sedentary donors. Untargeted metabolomics reveal metabolites enriched in cecal content, serum, and muscle of recipients from exercise-trained donors, consistent with microbial origin. Oral administration of two such metabolites (pipecolic acid and succinate) attenuates muscle atrophy and preserves muscle function in exercise-naïve mice, potentially by enhancing cellular energy status and translational capacity. These findings further define the gut microbiome-skeletal muscle axis and provide evidence that exercise-associated microbial metabolites serve as a novel class of exercise mimetics for treating conditions responsive to physical activity.
    DOI:  https://doi.org/10.1038/s41467-026-74852-w
  7. Acupunct Med. 2026 Jul 07. 9645284261462570
    Electroacupuncture ameliorates disuse muscular atrophy and inhibits the NLRP3 inflammasome and SIRT1 through miR-133a in a mouse model.
    Xing Cai, Yalian Zhang, Zhong Yang, Yuan Jiang, Bin Shu.
       OBJECTIVE: The aim of this study was to explore the potential role of microRNA (miR)-133a, the nucleotide-binding oligomerization domain, leucine-rich repeat family pyrin domain-containing 3 (NLRP3) inflammasome and Sirtuin1 (SIRT1) in the effects of electroacupuncture (EA) on disuse muscular atrophy in mice.
    METHODS: C2C12 cells were analyzed for protein expression of NLRP3, SIRT1, myogenin (MyoG) and myosin heavy chain protein (MyHC) after being transfected with a miR-133a-1 mimetic or miR-133a-3p inhibitor. Disuse muscular atrophy was induced in mice by tail suspension, and the mice either remained untreated (DA group) or received EA (frequency 20 Hz, intensity 1 mA, 15 min per day). The morphology of skeletal muscle was measured by muscle/body weight ratios, muscle fiber cross-sectional area (CSA) and expression of Atrogin-1 and Muscle RING finger-1 (MuRF1). miR-133a, NLRP3, apoptosis-associated speck-like protein (ASC), caspase-1 and SIRT1 were detected sequentially. Differentiation of skeletal muscle was examined by measurement of MyoG and MyHC.
    RESULTS: In our in vitro experiments, overexpression of miR-133a downregulated the expression of NLRP3 and SIRT1, and upregulated the expression of MyoG and MyHC. In our in vivo experiments, EA effectively ameliorated muscle wet weight and fiber CSA in the mouse model of disuse muscular atrophy, and decreased Atrogin-1 and MuRF1. EA also significantly increased the expression of miR-133a, inhibited the expression of NLRP3, ASC, caspase-1 and SIRT1, and increased the expression of MyoG and MyHC.
    CONCLUSIONS: These results indicate that EA-induced reductions of disuse muscular atrophy may be related to miR-133a. First, miR-133a may inhibit NLRP3 inflammasome activation to reduce muscle loss. Second, miR-133a may regulate SIRT1 expression to induce skeletal muscle differentiation and potentially promote muscle tissue recovery.
    Keywords:  NLRP3 inflammasome; SIRT1; disuse muscular atrophy; electroacupuncture; miR-133a
    DOI:  https://doi.org/10.1177/09645284261462570
  8. Front Aging. 2026 ;7 1830839
    Mitochondrial transcription factor A: linking mtDNA maintenance, mitochondrial stress responses, and inflammaging.
    Nengneng Shi, Xiaojing Li.
      Mitochondrial transcription factor A (TFAM) is a nuclear-encoded mitochondrial protein that directly binds mitochondrial DNA (mtDNA) and contributes to mitochondrial genome maintenance. Beyond its established roles in mitochondrial transcription, mtDNA packaging, nucleoid organization, replication support, and copy number control, TFAM is increasingly recognized as a potential regulator of aging-related mitochondrial stress responses. Because mtDNA instability, respiratory dysfunction, reactive oxygen species imbalance, impaired autophagy, cellular senescence, and chronic inflammation are closely interconnected during aging, TFAM may occupy a proximal position linking mitochondrial genome homeostasis to broader aging biology. However, TFAM should not be viewed as a uniformly protective factor. Its effects appear to depend on TFAM abundance, TFAM-to-mtDNA stoichiometry, tissue type, metabolic state, mitochondrial import, LONP1-mediated turnover, and mitochondrial quality-control capacity. TFAM deficiency may compromise mtDNA maintenance, impair oxidative phosphorylation, increase mitochondrial ROS production, and promote mtDNA-driven innate immune activation. Conversely, excessive or dysregulated TFAM accumulation may lead to mtDNA hypercompaction, reduce mtDNA accessibility, and potentially produce maladaptive effects in specific disease contexts. In this review, we discuss the structural basis of TFAM-mtDNA interaction, the role of TFAM in mtDNA transcription, copy number control, genome protection, damage handling, inflammatory signaling, cellular senescence, systemic aging, and age-related diseases. We also highlight therapeutic opportunities, limitations, and unresolved questions, emphasizing that future strategies should aim to restore TFAM homeostasis rather than simply increase TFAM expression.
    Keywords:  age-related disease; aging; inflammation; mitochondria; mitochondrial transcription factor A; oxidative stress
    DOI:  https://doi.org/10.3389/fragi.2026.1830839
  9. Nucleic Acids Res. 2026 Jul 03. pii: gkag700. [Epub ahead of print]54(13):
    Trans-species microRNAs from the parasitic plant Cuscuta campestris specifically avoid loading onto self Argonautes.
    Ya-Chi Nien, Cole D Caron, Paulina J Frutos, Francesca M Veltri, Michael J Axtell.
      The obligate parasitic plant Cuscuta campestris delivers trans-species microRNAs (miRNAs) into host plants that silence host mRNAs. Here, the genetic requirements for biogenesis, movement, and function of these miRNAs were investigated. Primary miRNA transcript accumulation precedes mature miRNA accumulation by 24 to 48 h. Trans-species miRNAs accumulate in host tissues a short distance from the site of parasite attachment. Trans-species miRNAs require C. campestris but not host Dicer-Like 1 (DCL1) for accumulation. These miRNAs specifically avoid Argonaute (AGO) loading in C. campestris tissue where they instead accumulate as miRNA/miRNA* duplexes. After arrival and short-distance spreading in host tissues, they are loaded onto host AGO proteins, including AGO1 and AGO2. This study clarifies the transcription, dicing, delivery, and function of C. campestris trans-species miRNAs. We propose that selective avoidance of self-AGO loading is a mechanism to facilitate high rates of delivery of these "export only" miRNAs to host tissues.
    DOI:  https://doi.org/10.1093/nar/gkag700
  10. bioRxiv. 2026 Jun 29. pii: 2026.06.24.734305. [Epub ahead of print]
    Intestinal lipid metabolism controls immune response through NHR-68 and gut-brain signaling in C. elegans.
    Jie Ren, Yu Sang, Young-Mo Kim, Ernesto S Nakayasu, Alejandro Aballay.
      Animals must allocate limited energetic resources across competing defense programs in response to infection. Here, we show that the conserved nuclear hormone receptor NHR-68 integrates fatty acid metabolism with the neural control of molecular and behavioral immunity in Caenorhabditis elegans . Acting in parallel with NHR-10, NHR-68 controls genes involved in polyunsaturated fatty acid (PUFA) metabolism. Loss of NHR-68 disrupts linoleic acid (LA) homeostasis, impairing pathogen avoidance behavior. Supplementation with LA restores avoidance, and fat-3 inhibition, which elevates LA, enhances pathogen avoidance, whereas loss of LA synthesis by fat-2 inhibition diminishes this behavior, indicating that LA promotes behavioral immunity. We further show that NHR-68 acts in the intestine to regulate linoleic acid homeostasis, and that changes in intestinal lipid metabolism influence an AWC-dependent pathogen-avoidance circuit through intestine-to-neuron communication. NHR-68 suppresses activation of the PMK-1/p38 MAPK and DAF-16/FOXO pathways, which mediate molecular immune responses. These findings identify a gut-brain transcriptional circuit that connects intestinal lipid metabolism to neural and immune outputs, revealing a mechanism by which the metabolic state coordinates behavioral and molecular defenses to optimize host protection.
    DOI:  https://doi.org/10.64898/2026.06.24.734305
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