bims-musmir Biomed News
on microRNAs in muscle
Issue of 2026–08–23
twelve papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. Histopathology and spatial transcriptomics jointly map myofiber-specific pathological programs in mTORC1-driven myopathy.
  2. Antisense oligonucleotides against Il6ra ameliorate cancer cachexia in mice.
  3. Aged Mitochondrial DNA Is Associated With Aberrant Acute Exercise-Induced Redox Responses in Human Skeletal Muscle.
  4. The hallmarks of skeletal muscle health.
  5. miR-15a-3p promotes excessive autophagy and drives skeletal muscle atrophy in sepsis.
  6. A phlorotannin-rich seaweed extract activates AMPK/PGC-1α signaling and antioxidant defences in skeletal muscle cells.
  7. Cytoplasmic DNA Sensing Links LINE-1 Expression to Neuronal Senescence in Alzheimer's Disease.
  8. MiRQuery: a user-friendly web app for the interactive analysis and visualization of microRNA sequencing data.
  9. Bridging LysoPD and MitoPD: Lysosomal pH Links Two Hallmarks of Parkinson's Disease.
  10. i.c.v. delivery of AAV9-synapsin-promoted caveolin-1 attenuates neuromuscular deficits and neuromuscular degeneration in hSOD1G93A mice.
  11. NAMPT activation uncovers a senescence-specific vulnerability and promotes healthy aging in combination with NAM.
  12. Multiple molecular pathways to longevity with opposing gene expression programs defining distinct aging strategies in Caenorhabditis elegans.
  1. JCI Insight. 2026 Aug 20. pii: e203167. [Epub ahead of print]
    Histopathology and spatial transcriptomics jointly map myofiber-specific pathological programs in mTORC1-driven myopathy.
    Jer-En Hsu, Qingyang Zhao, Weiqiu Cheng, Hyun Min Kang, Susan V Brooks, Myungjin Kim, Jun Hee Lee.
      Skeletal muscle is composed of heterogeneous myofiber types and non-myocyte populations. Myopathies occur in many diseases, but mechanisms driving these pathologies remain largely unknown, partly because conventional approaches cannot link histopathological features to molecular states at single-fiber resolution. To address this challenge, we brought histopathology and spatial transcriptomics together by applying high-resolution Seq-Scope technology to a mouse model of mTORC1 hyperactivation. Cross-sections from extensor digitorum longus (EDL) and soleus (SOL), two muscles with distinct fiber-type compositions, were profiled to determine how transcriptome changes are linked to histopathological outcomes. mTORC1 hyperactivation elicited distinct, fiber-type-dependent pathological programs. Type I and IIa fibers were largely resistant to mTORC1-induced pathology, exhibiting relatively limited morphological alterations. In contrast, type IIx fibers diverged into opposing fates: in SOL, they underwent abnormal enlargement associated with sustained growth signaling, cytoskeletal remodeling, and impaired proteostasis; in EDL, they developed basophilia associated with increased RNA content and lipid, oxidative, and nucleotide metabolism-related signatures. Within EDL, type IIb fibers displayed heterogeneity with discrete transcriptional states. Non-myocytic populations, including macrophages and fibroblasts, accumulated preferentially in SOL, forming a fibrotic microenvironment associated with inflammation, remodeling, and hypertrophy. These findings provide a link between histopathological phenotypes and molecular states at single-fiber resolution.
    Keywords:  Autophagy; Cell biology; Muscle biology; Skeletal muscle; Transcriptomics
    DOI:  https://doi.org/10.1172/jci.insight.203167
  2. Mol Ther. 2026 Aug 19. pii: S1525-0016(26)00709-4. [Epub ahead of print]
    Antisense oligonucleotides against Il6ra ameliorate cancer cachexia in mice.
    Yuanyuan Wang, Qingtao Sun, Wenqiang Zheng, Lijie Han, Qian Zhang, Adrian R Krainer, Bo Li.
      Mounting evidence indicates that interleukin-6 (IL-6) plays an essential role in the development of cancer cachexia. Particularly, recent work showed that IL-6 drives cancer cachexia through neurons in the area postrema of the brainstem. However, there are currently no approved drugs for treating cancer cachexia. Here we developed a splice-switching antisense oligonucleotide (ASO)-based therapy for treating cancer cachexia by reducing IL-6 receptor (IL-6R) expression in the brain. In two mouse models of cancer cachexia, a single dose of ASOs, administered by intracerebroventricular injection after cancer onset, reduces IL-6R levels in the brainstem and ameliorates cachectic symptoms. It also extends survival in one of the models. In parallel, the ASO treatment reduces cancer-associated transcriptomic activation of inflammatory pathways in both the brainstem and skeletal muscle. We also developed ASOs that suppress human IL-6R expression, paving the road for clinical studies. Our study thus provides a new approach for treating cancer cachexia.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.08.028
  3. Aging Cell. 2026 Sep;25(9): e70678
    Aged Mitochondrial DNA Is Associated With Aberrant Acute Exercise-Induced Redox Responses in Human Skeletal Muscle.
    Bradley A Ruple, Nicholas A Carlini, Jason S Kofoed, Helya Rostamkhani, Brady E Hanson, Jesse C Craig, Shelby C Osburn, Allison M Manuel, Paul A Stewart, Jonathan Wanagat, Ryan M Broxterman, Joel D Trinity.
      Redox imbalances and mitochondrial dysfunction are key contributors to age-related declines in skeletal muscle and may contribute to impaired exercise responsiveness. Here, we investigated the influence of aging on skeletal muscle redox at rest and in response to acute exercise, examining how mitochondrial quality and quantity relate to skeletal muscle redox status. Skeletal muscle biopsies were obtained from 12 young (22 ± 4 years) and 10 older adults (66 ± 7 years) before and immediately after 60-min of high-intensity knee-extension exercise. We assessed mitochondrial respiration, mitochondrial DNA (mtDNA) copy number and deletion mutation frequency at baseline, while skeletal muscle redox proteomics was performed on pre- and post-exercise biopsies in a subset of participants. Mitochondrial respiration was preserved with age (max respiration, p = 0.123). However, the older adults had a lower mtDNA copy number (p = 0.046) and higher mtDNA deletion frequency (p = 0.001), with widespread remodeling of the skeletal muscle redox proteome, including altered thiol occupancy of proteins involved in metabolism, immune function, and extracellular matrix organization. In response to exercise, young skeletal muscle exhibited predominantly reversible peptide reductions, whereas preferential oxidation of mitochondrial antioxidant proteins, including PRDX3, occurred in older muscle. Both mtDNA deletion frequency and mitochondrial respiration were strongly associated with exercise-induced redox modifications in mitochondrial proteins. These findings suggest that aging alters both the regulation and resolution of exercise-induced redox signaling, with mitochondrial genomic instability and respiration shaping redox responsiveness.
    Keywords:  aging; exercise; mitochondrial DNA; oxidative stress; redox proteomics
    DOI:  https://doi.org/10.1111/acel.70678
  4. Nat Metab. 2026 Aug 20.
    The hallmarks of skeletal muscle health.
    Anna Vainshtein, Bert Blaauw, Katrien De Bock, Pura Munoz-Canoves, Eric N Olson, Coen A C Ottenheijm, Erik A Richter, Jorge L Ruas, Laurent Schaffer, Bruce Spiegelman, Marco Sandri.
      Skeletal muscle is a central determinant of organismal health. Preserving muscle quality is therefore critical for preventing disease and sustaining quality of life across the lifespan. Despite its central role, the field lacks a unifying framework that defines the core properties of skeletal muscle health. Here, we propose a conceptual framework for muscle homeostasis built around seven interconnected hallmarks-metabolism and bioenergetics, proteostasis, genomics, excitability, structure, regeneration and cross-talk-that collectively govern muscle integrity, adaptability and resilience. Each hallmark is mechanistically grounded, quantifiable and potentially modifiable. This framework provides a unifying blueprint for the next generation of precision diagnostics and targeted therapies for preserving skeletal muscle health.
    DOI:  https://doi.org/10.1038/s42255-026-01595-9
  5. Shock. 2026 Aug 18.
    miR-15a-3p promotes excessive autophagy and drives skeletal muscle atrophy in sepsis.
    Ling-Ling Zhou, Shu-Li Zhang, Wei-Qing Xiao, Xiao-Yong Zhang, Xiao-Yan Zhu, Peng-Xiang Wang, Yu-Jian Liu.
      Approximately 50% of sepsis patients develop acute skeletal muscle atrophy and dysfunction. Autophagy plays an important role in skeletal muscle atrophy and dysfunction, and skeletal muscle autophagy is known to be regulated by multiple miRNAs. In this study, we found that miR-15a-3p was significantly upregulated in published Gene Expression Omnibus (GEO) datasets of septic patients and septic mouse skeletal muscle. Correlation analysis revealed that miR-15a-3p was associated with autophagy activation in septic patients and septic mouse skeletal muscle. Inhibition of miR-15a-3p attenuated excessive autophagy and ameliorated skeletal muscle atrophy in septic mice and differentiated C2C12 myotubes. Overexpression of miR-15a-3p increased autophagy and skeletal muscle atrophy in mice and differentiated C2C12 myotubes. Furthermore, we identified peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as a direct target of miR-15a-3p. Our findings elucidate the molecular mechanisms underlying miR-15a-3p in sepsis-induced autophagy and skeletal muscle injury, highlighting its potential as a therapeutic target.
    Keywords:  PGC1α; autophagy; microRNA-15a-3p; sepsis; skeletal muscle atrophy
    DOI:  https://doi.org/10.1097/SHK.0000000000002924
  6. In Vitro Cell Dev Biol Anim. 2026 Aug 19.
    A phlorotannin-rich seaweed extract activates AMPK/PGC-1α signaling and antioxidant defences in skeletal muscle cells.
    Anaïs Marandeau, Morgane Pengam, Solène Connan, Valérie Stiger-Pouvreau, Laurence Meslet-Cladière, Marie-Dominique Jezequel, Hélène Talarmin, Aline Amérand.
      Sedentary behaviour, ageing and chronic diseases represent major public health burdens associated with impaired skeletal muscle function and increased oxidative stress. Identifying bioactive compounds capable of mimicking the molecular adaptations induced by physical exercise therefore constitutes a relevant pharmacological strategy. Phlorotannins, polyphenolic compounds exclusively biosynthesised by brown macroalgae, are promising candidates owing to their antioxidant and metabolic properties. This study aimed to characterise a phlorotannin-enriched ethyl acetate extract from Halidrys siliquosa (HS extract) and assess its pharmacological properties in L6 rat myoblasts, a well-established skeletal muscle cell model. Chemical profiling by LC-MS and NMR identified carmalol- and fuhalol-type derivatives, two subclasses of phlorotannins, as predominant constituents, with strong radical scavenging activity in the DPPH assay. HS extract was non-cytotoxic at 1 and 10 µg/mL and did not alter basal ROS levels after 24-h treatment. At the molecular level, HS extract significantly increased the P-AMPK/AMPK ratio and PGC-1α transcript levels, two key mediators of exercise-induced metabolic adaptation, and enhanced glutathione peroxidase (GPx) enzymatic activity, indicating reinforced antioxidant defences. In a preventive setting, HS extract pretreatment markedly reduced H₂O₂-induced cell death and ROS overproduction. Collectively, these findings demonstrate that HS extract activates exercise-associated metabolic signaling pathways in rat skeletal muscle cells. These results suggest that HS extract may represent a promising source of bioactive compounds capable of modulating exercise-related molecular responses, warranting further investigation in differentiated muscle models and in vivo studies.
    Keywords:   Halidrys siliquosa ; AMPK/PGC-1α signaling pathway; Antioxidant; Phlorotannins; Skeletal muscle cells
    DOI:  https://doi.org/10.1007/s11626-026-01230-7
  7. bioRxiv. 2026 Jul 28. pii: 2026.07.27.740588. [Epub ahead of print]
    Cytoplasmic DNA Sensing Links LINE-1 Expression to Neuronal Senescence in Alzheimer's Disease.
    Joseph R Herdy, Emma E Taylor, Lukas Karbacher, Oliver Borgogno, Larissa Traxler, Jessica Lagerwall, Vincent A Huynh, Zornitsa V Lefterova, Austin Kang, Carlota Tosat-Bitrian, Maxfield Kelsey, John Sedivy, Subhash Sinha, Li Gan, C Frank Bennett, Dylan A Reid, Jerome Mertens, Fred H Gage.
      Cellular senescence contributes to neurodegeneration in Alzheimer's disease (AD), yet brain-penetrant senotherapeutic strategies remain limited. Here, we identify long interspersed nuclear element 1 (LINE-1) retrotransposons as key regulators of neuronal senescence and the senescence-associated-secretory-phenotype (SASP) in AD. Using transdifferentiated induced neurons (iNs) that preserve donor-specific aging-associated molecular signatures, we show that pharmacological inhibition of LINE-1 with nucleoside reverse transcriptase inhibitors (nRTIs) or antisense oligonucleotides reduces p16 expression, suppresses SASP and interferon-stimulated gene programs, and attenuates paracrine induction of reactive astrogliosis. Spatial transcriptomic analysis of human AD brain tissue further supports that senescent neurons with high LINE-1 expression are localized to inflammatory niches in the brain. Although bulk analysis finds no significant differences in LINE-1 expression between AD and control neurons, long-read single-cell RNA sequencing of iNs identifies a subset of neurons with elevated LINE-1 activity which display transcriptional signatures of neurodegeneration, immune activation, and senescence are enriched in AD relative to controls. RNA velocity analysis indicates that LINE-1 activation precedes the induction of canonical senescence markers, supporting a causal rather than consequential role. Mechanistically, LINE-1-derived cytoplasmic DNA activates the cGAS-STING innate immune pathway in post-mitotic neurons, and inhibition of cGAS phenocopies the effects of LINE-1 suppression. Together, these findings establish a LINE-1/cGAS-STING axis as a driver of neuronal senescence in AD and highlight LINE-1 inhibition as a tractable senomorphic strategy for neurodegenerative disease.
    DOI:  https://doi.org/10.64898/2026.07.27.740588
  8. BMC Bioinformatics. 2026 Aug 17. pii: 184. [Epub ahead of print]27(1):
    MiRQuery: a user-friendly web app for the interactive analysis and visualization of microRNA sequencing data.
    Julianne C Yang, Jake Sauter, Gregory C Adam, Richard Carr.
       BACKGROUND: MicroRNAs (miRNAs) are a class of small noncoding RNAs that inhibit the translation of target messenger RNAs (mRNAs). Given that a single miRNA can regulate the translation of many mRNAs, miRNAs have emerged as critical regulators of physiological processes. MiRNAs have been linked to the development and progression of cancers, neurodegenerative and other diseases, most recently using high-throughput miRNA "miRNome" sequencing. As miRNome sequencing represents a newer 'omics application, limited guidance is available for how to analyze this data. Existing interfaces that enable non-computational users to interpret and perform comprehensive secondary analysis on their own miRNome data are limited in functionality and/or interactivity. Therefore, we developed MiRQuery to address this need.
    RESULTS: MiRQuery is an RShiny application which features common visualization methods for high-throughput sequencing data, such as multidimensional scaling, stacked column charts, heatmaps, and boxplots to compare expression across groups for a user-specified miRNA of interest. MiRQuery further provides support for differential miRNA and gene expression analysis. Unique to miRNome sequencing data analysis, users may retrieve predicted gene targets of differentially expressed miRNA and follow up with pathway overrepresentation analysis of the gene targets. Finally, if users upload paired bulk mRNA sequencing data, they may identify differentially expressed genes and negatively correlated miRNA-gene pairs.
    CONCLUSIONS: By providing access to sophisticated bioinformatics tools through a user-friendly interface, MiRQuery empowers both scientists new to bioinformatics and bioinformaticians new to the field to extract insights rapidly and reproducibly from their sequencing data. MiRQuery can be accessed through PositConnect at https://julianneyang-mirquery.share.connect.posit.cloud/ , and alternatively is available by user local installation via instructions on the Github project homepage.
    Keywords:  High-throughput sequencing; Next-generation sequencing; RShiny; miRNA; miRNome; miRnomics
    DOI:  https://doi.org/10.1186/s12859-026-06479-z
  9. Mov Disord. 2026 Aug 18.
    Bridging LysoPD and MitoPD: Lysosomal pH Links Two Hallmarks of Parkinson's Disease.
    Hari Prasad.
      
    Keywords:  GBA1; Parkinson's disease; lysosomal pH; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.1002/mds.70492
  10. Mol Ther Adv. 2026 Sep 10. 34(3): 201820
    i.c.v. delivery of AAV9-synapsin-promoted caveolin-1 attenuates neuromuscular deficits and neuromuscular degeneration in hSOD1G93A mice.
    Noriyuki Watanabe, Yumi Kawahori, Vinh Ta, Dongsheng Wang, Kenneth A Ohgi, Hongxia Wang, Natalia Kleschevnikova, Eiichi Ishikawa, Brian P Head.
      Practical and broad biodistributable gene delivery interventions are essential for advancing therapeutic strategies targeting neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously demonstrated that subpial delivery of AAV9-synapsin-promoted caveolin-1 (SynCav1) afforded significant neuroprotective effects in mutant superoxide dismutase (SOD)-1-induced ALS pathology. However, subpial delivery is regionally restricted, technically challenging, and highly invasive. This study evaluated whether the intracerebroventricular (i.c.v.) route of administration (ROA), an alternative CNS delivery strategy less invasive than direct spinal cord injections, could achieve broader CNS biodistribution and produce functional or histological benefits in hSOD1G93A mice. i.c.v. administration of AAV9-SynCav1 achieved widespread Cav-1 overexpression in the motor cortex and spinal cord. SynCav1-treated male mice exhibited improved running wheel (RW) performance and better motor-evoked potentials. Immunofluorescence revealed attenuated degeneration of cholinergic motor neurons (MNs) in the cervical and lumbar ventral horn, as well as preserved diaphragm neuromuscular junction (NMJ) innervation in SynCav1-treated mice. These findings serve as preclinical proof of concept that i.c.v. delivery of AAV9-SynCav1 can achieve CNS target engagement and produce selective functional and anatomical benefits in hSOD1G93A mice.
    Keywords:  AAV9-SynCav1; amyotrophic lateral sclerosis; caveolin-1; intracerebroventricular administration; motor neuron; neuroprotection
    DOI:  https://doi.org/10.1016/j.omta.2026.201820
  11. bioRxiv. 2026 Aug 07. pii: 2026.08.06.743365. [Epub ahead of print]
    NAMPT activation uncovers a senescence-specific vulnerability and promotes healthy aging in combination with NAM.
    Michael Alcaraz, Raghuveer Ramachandra, Rouven Arnold, Marcos Garcia-Teneche, Adarsh Rajesh, Laurence Haddadin, Mey Taing, Xue Lei, Armin Gandhi, Theophilos Tzaridis, Karl Miller, Jessica Proulx, Amirhossein Nayeri Rad, Andrew Davis, Angela Liou, Hiroshi Tanaka, Tumpa Dutta, Rebecca Poritt, Valentin Cracan, Colin Loweth, Steven Olson, Stephen J Gardell, Michael Jackson, Peter D Adams.
      Aging is driven by multiple interacting processes, suggesting that effective strategies to promote healthy aging may require simultaneous targeting of more than one underlying mechanism. Here we identify a strategy that couples restoration of nicotinamide adenine dinucleotide (NAD+) homeostasis with selective targeting of senescent cells, two mechanistically linked features of aging. Senescent cells express elevated intracellular levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the nicotinamide (NAM) salvage pathway for NAD+ biosynthesis. Despite increased NAMPT abundance, isotope-tracing studies revealed decreased NAD+ biosynthesis and consumption, indicating that elevated NAMPT abundance was not accompanied by a corresponding increase in NAD+ metabolic flux. Treatment with the NAMPT activator SBI-0802162 engaged the spare enzymatic capacity of NAMPT in senescent cells and produced a marked rise in intracellular NAD+ that, when sustained, disrupted their transcriptional program and selectively reduced the viability of senescent cells but not proliferating cells. In mice, SBI-0802162 reduced circulating NAM levels, suggesting that sustained NAMPT activation may be limited by substrate availability. This observation prompted the development of a combination approach using SBI-0802162 together with dietary NAM supplementation. Co-administration of SBI-0802162 and NAM robustly increased tissue NAD+, suppressed select age-associated inflammatory signatures and markers of cellular senescence in a tissue-specific manner. These molecular effects occurred alongside preserved physical performance in aged mice and reductions in food intake and body weight, which were observed whether SBI-0802162 was present in the chow or administered by oral gavage. Together, these findings establish a mechanistically integrated approach to target two convergent features of aging, NAD+ dysregulation and senescent cell accumulation, and support combined NAMPT activation and NAM supplementation as a strategy to promote healthy aging.
    DOI:  https://doi.org/10.64898/2026.08.06.743365
  12. Elife. 2026 Aug 20. pii: RP112139. [Epub ahead of print]15
    Multiple molecular pathways to longevity with opposing gene expression programs defining distinct aging strategies in Caenorhabditis elegans.
    Zenith D Rudich, Jiaxi Guan, Aura A Tamez Gonzalez, Grant F Booth, Sonja K Soo, Ulrich Anglas, Meeta Mistry, Megan M Senchuk, Jeremy M Van Raamsdonk.
      While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. Our previous work has shown that targeting aging pathways can be neuroprotective in animal models of neurodegenerative disease. Based on these findings, we believe that by gaining insight into the aging process that knowledge can be applied to identify novel therapeutic targets for neurodegenerative disease. To advance our understanding of aging, we used a genomics approach to identify genes regulated by multiple lifespan-extending pathways. We performed RNA sequencing on nine long-lived Caenorhabditis elegans mutants representing seven longevity pathways: insulin/IGF-1 signaling, dietary restriction, germline deficiency, impaired chemosensation, reduced translation, elevated mitochondrial ROS, and mild mitochondrial impairment. We found that most pairs of long-lived mutants exhibited a significant overlap in differentially expressed genes. Comparing gene expression across the entire panel of long-lived mutants revealed three distinct longevity groups that could be clearly distinguished by gene expression. Interestingly, two of these groups showed modulation of specific genetic pathways in opposite directions, suggesting that there are multiple alternative strategies to achieving long life. Filtering for genes similarly modulated in at least six mutants identified 196 upregulated and 62 downregulated aging genes. Upregulated genes were enriched in immunity, defense, and metabolism, while many downregulated genes impacted translation and gene expression. To assess the ability of these genes to enhance longevity individually, we knocked down the commonly upregulated genes in long-lived mutants and evaluated the resulting effect on lifespan. Using this approach, we identified several genes that affect lifespan individually. Upregulation of at least some of these genes was sufficient to enhance stress resistance and extend lifespan in wild-type worms. Overall, the shared longevity genes identified in this work offer potential targets to promote healthy aging and decrease age-onset disease.
    Keywords:  C. elegans; RNA sequencing; aging; biological resilience; developmental biology; genetics; genomics; lifespan; transcriptomics
    DOI:  https://doi.org/10.7554/eLife.112139
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