bims-musmir 2026-08-30 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–08–30
fifteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Tumor-educated adipocytes promote muscle wasting via EV-packaged miR-221-3p targeting IRS1 in pancreatic cancer cachexia.
Mitochondrial Ca2+ Influx via MCU-1 Contributes to Oxidative Mitochondrial Defects in PDR-1/Parkin-Deficient Caenorhabditis elegans Body-Wall Muscle.
The Role of Skeletal Muscle Mitochondria in NLRP3 Inflammasome Signaling.
The miRNA Argonaute protein, ALG-2, maintains neurobehaviors in adult C. elegans.
Musculoskeletal (Mal)adaptations in Response to a > 30 000-km Running Challenge.
Enhancing lysosome function via TFEB activation reduces lipofuscin-like granules in the retinal pigment epithelium.
Multi-omics identifies promoter methylation and gene expression changes associated with human skeletal muscle atrophy.
A Contemporary Pathomechanistic Nosology of Inherited Lysosomal Disorders.
Massively parallel characterization of RNA G-quadruplex stability and molecular recognition.
Identification of a CSC-Associated miRNA Signature in NSCLC and Functional Characterization of hsa-let-7a-3p.
cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation.
Skeletal Muscle Dysfunction and Exercise Intolerance in COPD and Idiopathic Pulmonary Fibrosis: Extracellular Vesicles as Candidate Mediators of a Lung-Muscle Axis.
Zinc increases stress granule formation by promoting RNA condensation.
Stable clocks, rewired rhythms: circadian remodeling in skeletal muscle during aging, cachexia, and type 2 diabetes.
Codon-optimized Npc1 mRNA corrects Niemann-Pick type C1 disease phenotypes in vitro and in vivo.

Cancer Lett. 2026 Aug 22. pii: S0304-3835(26)00559-8. [Epub ahead of print]659 218795

Tumor-educated adipocytes promote muscle wasting via EV-packaged miR-221-3p targeting IRS1 in pancreatic cancer cachexia.

Wanli Liu, Aoyi Xiao, Jingcheng Zhang, Ruizhe Zhu, Liangrui Zhou, Sumei Zhang, Zixin Zhang, Jinyuan Wang, Dingyan Cao, Huanwen Wu, Xudong Liu, Xianlin Han, Wenming Wu.

  Pancreatic ductal adenocarcinoma (PDAC) is often burdened by cachexia, a metabolic disorder characterized by extensive and severe adipose tissue wasting and muscle atrophy that shortens life expectancy. While adipose depletion frequently coincides with myopathy, the precise molecular mediators by which remodeled adipocytes drive muscle atrophy remain largely undefined. Here, we delineated a pathogenic 'feed-forward' axis wherein tumor-derived inflammatory stimuli (IL-6/TNF-α) drove adipocytes to secrete extracellular vesicles (EVs) enriched with miR-221-3p. Genetic tracing confirmed that these EVs circulated systemically and were actively taken up by skeletal muscle. At the molecular level, EV-delivered miR-221-3p repressed IRS1, leading to the collapse of the PI3K-AKT survival cascade. Consequently, this inhibition triggered severe metabolic dysregulation by coupling impaired GLUT4-dependent glucose transport with heightened ubiquitin-proteasome activity, ultimately culminating in muscle atrophy. Silencing miR-221-3p via AAV-sponges or antagomirs conferred significant protection against muscle wasting and functional decline in cachectic mice. Importantly, high levels of circulating EV-miR-221-3p not only marked the presence of cachexia but were also significantly associated with reduced overall survival in PDAC patients. Collectively, our findings uncover a pathogenic adipose-to-muscle axis mediated by EV-miR-221-3p, offering a novel therapeutic target and a promising non-invasive biomarker for PDAC-associated cachexia.

Keywords:  Adipose tissue remodeling; Cancer cachexia; Extracellular vesicles; Muscle wasting; Pancreatic ductal adenocarcinoma; miR-221-3p

DOI:  https://doi.org/10.1016/j.canlet.2026.218795
Antioxidants (Basel). 2026 Aug 21. pii: 1043. [Epub ahead of print]15(8):

Mitochondrial Ca2+ Influx via MCU-1 Contributes to Oxidative Mitochondrial Defects in PDR-1/Parkin-Deficient Caenorhabditis elegans Body-Wall Muscle.

Masahiro Kawasumi, Mika Teranishi.

  Parkinson's disease (PD) is widely regarded as a disorder of dopaminergic neurons that involves mitochondrial dysfunction, impaired mitophagy, and oxidative stress. However, the nature and significance of skeletal muscle pathology remain unclear. In this study, we used Caenorhabditis elegans, which lack muscle stem cells in adulthood, to examine the effects of PDR-1/Parkin deficiency on mitochondrial homeostasis and motor function under conditions where muscle regeneration does not occur. Silencing of pdr-1 attenuated age-related mitochondrial fragmentation in body-wall muscle cells but was associated with later impairments in locomotor activity and loss of nuclear GFP signals, suggesting progressive muscle cell damage. By day 2 of adulthood, mitochondrial reactive oxygen species (mtROS) levels were elevated in muscle cells subjected to pdr-1 RNAi, and in the pdr-1(gk448) mutant this mtROS elevation was accompanied by a reduction in mitochondrial membrane potential (ΔΨm). In vivo imaging further revealed elevated mitochondrial Ca2+ levels ([Ca2+]mito) in PDR-1-deficient muscle cells. Moreover, the mtROS increase associated with PDR-1 deficiency was suppressed in mcu-1 mutants. These findings support a model in which MCU-1-dependent elevation of [Ca2+]mito contributes to oxidative mitochondrial defects in PDR-1/Parkin-deficient muscle.

Keywords:  Caenorhabditis elegans; Parkinson’s disease; body-wall muscle cells; mitochondrial calcium influx; mitochondrial membrane potential; mitochondrial quality control; mitochondrial reactive oxygen species

DOI:  https://doi.org/10.3390/antiox15081043
Biomolecules. 2026 Aug 20. pii: 1218. [Epub ahead of print]16(8):

The Role of Skeletal Muscle Mitochondria in NLRP3 Inflammasome Signaling.

Jada Sangha, David A Hood.

  Skeletal muscle mitochondria possess the ability to autoregulate their health and functioning by the orchestration of mitochondrial quality control (MQC) pathways. This plasticity allows them to adapt to various stimuli, such as exercise. However, under pathological conditions, mitochondria can become dysfunctional, generating damage-associated molecular patterns (DAMPs), such as reactive oxygen species (ROS) and oxidized mitochondrial DNA (mtDNA). These DAMPs can launch an innate immune response, with consequences of widespread inflammation and atrophy. Integral to this is the NLRP3 inflammasome complex. Activation of the NLRP3 inflammasome results in maturation of caspase-1, which processes pro-inflammatory cytokines IL-1β and IL-18, as well as GSDMD. Consequently, the pore-forming GSDMD-N fragment induces pyroptosis, releasing mature IL-1β and IL-18. Exercise training is widely accepted as a potent mechanism to promote skeletal muscle health, particularly by remodeling the mitochondrial network and reducing the production of DAMPs. It has also been shown promote an anti-inflammatory milieu with the release of various myokines. Indeed, the potential of exercise to mitigate NLRP3 inflammasome-mediated inflammation and atrophy is promising. This review will examine the mechanisms underpinning inflammasome priming and activation, as well the effects of exercise, with an emphasis on the skeletal muscle.

Keywords:  NLRP3 inflammasome; exercise; inflammation; mitochondria; mtROS; muscle atrophy; skeletal muscle

DOI:  https://doi.org/10.3390/biom16081218
MicroPubl Biol. 2026 ;2026

The miRNA Argonaute protein, ALG-2, maintains neurobehaviors in adult C. elegans.

Ava Chon, Runtian Jiang, Yuxuan Guo, Yamin K Phyu, Lilly M Goldberg, Erin C Schiksnis, Amy E Pasquinelli, Sierra D Palumbos.

microRNAs (miRNAs) are short, non-coding RNAs essential for gene regulation in many different processes, including neuronal development. However, the role of the miRNA pathway in maintaining neuronal health throughout aging is less understood. Here, we ask how the miRNA pathway in adulthood impacts neurobehaviors in C. elegans . Argonaute-like Gene 2 ( ALG-2 ) is a protein required for the accumulation and function of certain miRNAs in C. elegans . Using the auxin-inducible degron 2 (AID2) system for temporal knockdown, we demonstrate that the miRNA Argonaute protein, ALG-2 , is required throughout adulthood to maintain two well-characterized neurobehaviors, basal slowing response and mechanosensation.

DOI: https://doi.org/10.17912/micropub.biology.002217
J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70368

Musculoskeletal (Mal)adaptations in Response to a > 30 000-km Running Challenge.

Tomas Venckunas, Thomas Chaillou, Leonardo Cesanelli, Danguole Satkunskiene, Saulius Rutkauskas, Audrius Snieckus, Petras Minderis, Darja Nikitina, Jurgita Skieceviciene, Juozas Kupcinskas, Lorenz Webersberger, Johanna T Lanner, Mantas Mickevicius, Birutė Gumauskiene, Asta Kuzmickaite, Andrejus Subocius, Sigitas Kamandulis.

   BACKGROUND: Ultra-endurance sports are increasingly popular, yet the long-term physiological consequences of sustained extreme training loads remain poorly understood. In particular, the effects of prolonged ultra-endurance exercise on skeletal muscle structure, function and molecular remodelling are largely unknown. This case study examined a highly experienced ultra-endurance athlete who completed a world-record attempt to run 30 300 km, with extensive phenotyping focusing on skeletal muscle adaptations and recovery.
METHODS: A 49-year-old male athlete (172 cm, 65 kg) ran ~70 km daily for 15 months. Musculoskeletal, cardiac and visceral ultrasonography, leg muscle strength and power measurements were performed before and after the challenge. Muscle biopsies (n = 4) from vastus lateralis were obtained immediately after completion and during 17 months of recovery to assess myosin heavy chain (MHC) composition, mitochondrial electron transport chain (ETC) complexes and proteins involved in mitochondrial turnover, autophagy and inflammation. Body composition, haematological and biochemical markers, and gut microbiota composition were monitored longitudinally.
RESULTS: The athlete ran 30 300 km over 444 days, maintaining a daily distance of ~70 km despite substantial musculoskeletal discomfort, including a tibial stress reaction mid-challenge, which resolved gradually with continued running. Body mass decreased by ~3 kg, primarily reflecting fat loss (~83%), accompanied by reductions in muscle thickness, maximal strength and power. Circulating creatine kinase (3-15-fold), oxidative stress markers (~50%) and GDF8 (~10%-50%) were sustainedly increased, whereas IGF-I decreased (~10%-40%), suggesting a reduced anabolic environment during the challenge. Muscle biopsy analyses revealed a progressive recovery of mitochondrial function during the 17 months following the challenge, as evidenced by a progressive increase in ETC protein abundance and the expression of regulators of mitochondrial dynamics and quality control (MFN2, PARKIN, DRP1). In contrast, markers of autophagy, apoptosis and inflammation were decreased during the 17-months post-challenge (LC3A/B-I by ~50%, CASP3 by ~60% and NF-κBSer536 by ~20%). Muscle fibre composition showed extreme predominance of slow fibres (nearly 100% MHC-I), which persisted during recovery. Most molecular and functional alterations gradually resolved within 10-17 months. Gut microbiota diversity increased during the challenge, with enrichment of Bifidobacterium during running and Akkermansia during recovery.
CONCLUSIONS: Sustaining daily ultrarunning for more than 1 year induces substantial skeletal muscle remodelling, including reduced muscle size, impaired contractile function and mitochondrial maladaptations, despite largely preserved endocrine and haematological stability. These findings highlight skeletal muscle as a primary physiological system challenged during extreme endurance exercise and demonstrate that recovery from such perturbations may require more than one year.

Keywords:  MHC composition; gut microbiota; mitochondrial function; muscle wasting; skeletal muscle; ultra‐endurance

DOI:  https://doi.org/10.1002/jcsm.70368
Exp Eye Res. 2026 Aug 24. pii: S0014-4835(26)00371-4. [Epub ahead of print] 111215

Enhancing lysosome function via TFEB activation reduces lipofuscin-like granules in the retinal pigment epithelium.

Ana S Falcão, Mafalda Lopes-da-Silva, Pedro Antas, Cristina Escrevente, Margarida Pedro, Beatriz Felgueiras, Beatriz Caires, Rita Coelho, Inês S Ferreira, Inês P Santos, Thomas Ciossek, Paul Nicklin, Sandra Tenreiro, Miguel C Seabra.

  Age-related macular degeneration (AMD) is the most common blinding disease in the western world and is currently incurable. Although the exact causes of AMD are not clear, the primary origin of pathology appears to be the aged retinal pigment epithelium (RPE) exhibiting signs of lysosomal dysfunction and oxidative damage. RPE is responsible for the daily digestion of photoreceptor outer segments (POS), imposing a heavy continuous burden on the lysosomal network. A cellular model of RPE lysosomal dysfunction can be achieved by feeding RPE with a single pulse of POS, leading to the accumulation of autofluorescence granules (AFG), similar to lipofuscin in vivo. Here we show that synchronous phagocytosis of POS leads to early transient mTOR activation followed by inhibition in late phagosome maturation. One of its substrates, the transcription factor EB (TFEB) increases during phagosome maturation albeit mostly in its inactive phosphorylated form. We questioned whether modulation of the mTOR/TFEB axis could improve POS clearance and hence reduce AFG load. Treatment of POS-fed cells after the appearance of AFGs with rapamycin, an mTORC1 inhibitor results in ∼30% reduction of AFG load. This effect is dependent on active lysosomal enzymes and induction of active dephosphorylated TFEB with consequent activation of GADD34 and lysosomal biogenesis. As a proof of concept, we show that overexpressing a constitutively active form of unphosphorylated TFEB dramatically reduces POS-dependent AFG accumulation. Overall, this study suggests that viral or pharmacological approaches activating the TFEB pathway in the RPE could be beneficial as cell-protective treatment of early/intermediate cases of AMD, acting to delay progression of the disease.

Keywords:  TFEB; autofluorescent granules; lysosomal dysfunction; mTOR; photoreceptor outer segments phagocytosis

DOI:  https://doi.org/10.1016/j.exer.2026.111215
Exp Physiol. 2026 Aug 24.

Multi-omics identifies promoter methylation and gene expression changes associated with human skeletal muscle atrophy.

Jamie-Lee M Thompson, Thomas M Doering, Boris P Budiono, Kristen L Mackenzie-Shalders, Kevin J Ashton, Paul J Dunn, Vernon G Coffey.

  Skeletal muscle atrophy is a secondary complication in the aetiology of injury and chronic disease. Identifying mechanisms that control muscle mass is necessary to characterise atrophy and develop prevention strategies. We aimed to integrate transcriptomic and epigenomic data to identify key regulatory pathways controlled by promoter DNA methylation during muscle unloading. Twenty-one healthy men (20-40 years) completed a 4-week standardised exercise programme prior to a 14-day knee brace immobilisation with dietary control. Skeletal muscle mass and strength were assessed before and after immobilisation and biopsies were collected (m. vastus lateralis) before, at 3 days, and at completion at 14 days. RNA and DNA were isolated and analysed using Illumina RNA sequencing and DNA methylation 850K EPIC BeadChips. The 14-day immobilisation decreased muscle mass (∼9%; P < 0.0001) and strength (∼16%; P < 0.0001). At 3 days, most biological processes (BPs) were upregulated/hypomethylated (157 gene sets); upregulated BPs included cell signalling and protein ubiquitination and downregulated BPs included metabolism. After 14 days, BPs were predominantly downregulated/hypermethylated, including translation and ribosome biogenesis. Across both time points, HDAC4, GADD45A and CHRNA1 emerged as methylation-regulated candidate mediators of atrophy. HDAC4 and GADD45A showed strong correlations primarily at day 3, and CHRNA1 remained significant at both time points, extending prior observations in animals to human skeletal muscle. We have characterised changes in gene expression related to hypo- and hyper-methylation during muscle unloading in humans. These data extend our understanding of the regulatory processes that occur during skeletal muscle atrophy that, at the individual gene level, may be useful in developing strategies for reducing muscle wasting.

Keywords:  genetics; unloading; wasting

DOI:  https://doi.org/10.1113/EP093999
J Inherit Metab Dis. 2026 Sep;49(5): e70245

A Contemporary Pathomechanistic Nosology of Inherited Lysosomal Disorders.

Eamon P McCarron, Nenad Blau, Emily R Eden, Frances M Platt, Johannes M Aerts, Simon A Jones, Carlos R Ferreira, Karolina M Stepien.

  Lysosomal disorders (LDs) have traditionally been defined by intra-lysosomal substrate accumulation resulting from deficiencies of lysosomal enzymes or associated proteins. Advances in lysosomal biology have demonstrated that lysosomes function as central regulators of cellular signalling, membrane trafficking, autophagy, nutrient sensing, organelle communication and cellular homeostasis, expanding the spectrum of inherited disorders associated with lysosomal dysfunction beyond classical storage phenotypes. We developed a contemporary pathomechanistic nosology of inherited LDs through expert curation and targeted review of databases and published literature. Disorders were included when pathogenic variants resulted in lysosomal dysfunction as a major disease mechanism through defects affecting lysosomal degradation, membrane function, intracellular trafficking, biogenesis, autophagy-lysosome pathways or lysosome-related organelles. A total of 108 inherited lysosomal disorders caused by defects in 102 genes were identified and organised into 11 major disease categories. Neurologic and eye involvement were the most frequently affected organ-system categories, occurring in 80.6% and 68.5% of disorders, respectively. Digestive (including hepatosplenomegaly), dysmorphic, skeletal and haematological involvement occurred in 48.1%, 45.4%, 40.7% and 38.9% of disorders, respectively. Distinct phenotypic signatures were observed across disease categories despite substantial mechanistic overlap involving impaired autophagy, vesicular trafficking, lysosomal stress and altered organelle homeostasis. This proposed nosology extends disease classification beyond substrate accumulation alone and provides a biologically informed framework for disease classification, genomic interpretation, biomarker development, patient stratification and the development of mechanism-based therapies.

Keywords:  autophagy; disease classification; endolysosomal pathway; inherited lysosomal disorders; inherited metabolic disorders; lysosomal storage disorders; lysosome; nosology

DOI:  https://doi.org/10.1002/jimd.70245
Nucleic Acids Res. 2026 Aug 24. pii: gkag821. [Epub ahead of print]54(16):

Massively parallel characterization of RNA G-quadruplex stability and molecular recognition.

Justin G Martyr, Bryan B Guzmán, Alli Jimenez, Rebekah L Rothacher, Francisco F Cavazos, Yue Hu, Rhese D Thompson, Anthony M Mustoe, Maria M Aleman, Daniel Dominguez.

RNA G-quadruplexes (rG4s) have been implicated as important regulators of RNA metabolism and are promising targets for RNA-targeted therapeutics. rG4s typically require a canonical (G≥2N1-7)4 motif, but the sequence features that affect rG4 stability and recognition by RNA-binding proteins (RBPs) and rG4-binding ligands are not fully understood. To interrogate sequence-level drivers of rG4 folding, we applied a reverse-transcriptase stop sequencing strategy to a library of ∼3000 synthetic rG4s with varied G-tract lengths, loop lengths, and loop compositions, permitting massively parallel quantification of rG4 stability. Our data confirm known sequence-level features and characterize novel combinatorial impacts of these features. We also assessed systematically mutagenized natural rG4s, revealing unexpected mutations that significantly affect rG4 stability, including contributions from flanking sequences outside of the rG4. We further used our strategy to assess rG4 recognition preferences of the model rG4 ligand pyridostatin, revealing a preferential stabilization of rG4s containing mixed-length G-tracts. We additionally demonstrated the potential for large-scale protein-binding assays with our library to reveal rG4 features recognized by RBPs, specifically G3BP1 and FMRP. Our approach and data provide a generalizable framework to study sequence-level drivers of rG4 stability, binding by RBPs, and ligand interactions, defining basic principles of rG4 formation and downstream biology.

DOI: https://doi.org/10.1093/nar/gkag821
Biomedicines. 2026 Jul 31. pii: 1737. [Epub ahead of print]14(8):

Identification of a CSC-Associated miRNA Signature in NSCLC and Functional Characterization of hsa-let-7a-3p.

Ángela Y García Fonseca, Carlos Javier Alméciga-Díaz, Andrés F Aristizábal-Pachón.

  Background: Metastasis is the leading cause of mortality in lung cancer and is regulated by multiple molecular mechanisms, including microRNAs (miRNAs). Although cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) contribute to metastatic progression, the miRNA networks underlying these phenotypes remain poorly characterized in non-small cell lung cancer (NSCLC). Aim: To identify miRNA signatures associated with CSCs and EMT in NSCLC and functionally characterize hsa-let-7a-3p. Methods: EMT was induced in A549 and NCI-H1975 cells by dCas9-mediated activation of TWIST, whereas CSC-enriched populations were generated by CD133-based sorting and stem cell culture conditions. Small RNA sequencing, bioinformatic analyses, qPCR validation, and functional assays were performed to identify and characterize phenotype-associated miRNAs. Results: Small RNA sequencing identified distinct miRNA expression profiles associated with EMT and CSC enrichment. Comparative analysis identified 13 commonly downregulated and 13 commonly upregulated miRNAs shared by CSCs from A549 and H1975 cells, suggesting conserved post-transcriptional regulatory mechanisms. Functional enrichment and miRNA-target interaction network analyses linked the miRNA signatures to pathways involved in epithelial plasticity, stemness, and tumor progression, including Wnt, TGF-β, mTOR, focal adhesion, adherens junction, and regulation of the actin cytoskeleton. Among the dysregulated miRNAs, hsa-let-7a-3p was consistently upregulated in CD133+ CSC-enriched cells from both NSCLC cell lines. Functional assays showed that hsa-let-7a-3p overexpression significantly reduced clonogenic capacity and showed a trend toward decreased invasion without affecting proliferation. Conclusion: This study identifies miRNA signatures associated with CSC-enriched and EMT-associated phenotypes in NSCLC and demonstrates that these signatures represent coordinated post-transcriptional regulatory programs involved in epithelial plasticity, stemness, and metastatic progression. Functional validation of hsa-let-7a-3p further supports its role as a context-dependent regulator of CSC biology and highlights the potential of miRNA signatures as diagnostic biomarkers in NSCLC.

Keywords:  cancer stem cells; epithelial-to-mesenchymal transition; metastasis; miRNAs; non-small cell lung cancer

DOI:  https://doi.org/10.3390/biomedicines14081737
Nat Aging. 2026 Aug 25.

cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation.

John C Martinez, Francesco Morandini, Cheyenne Rechsteiner, Lucinda Fitzgibbons, Natasha Sieczkiewicz, Xiaoyan Liao, Weijie He, Sung Jae Bae, Michael E Meadow, Eric Hillpot, Joseph Cutting, Victoria Paige, Max Zacher, Seyed Ali Biashad, Matthew Simon, Ines Meula-Zarzuela, Mario D Cordero, Martin S Taylor, John M Sedivy, Andrei Seluanov, Vera Gorbunova.

Aging-associated inflammation is a driver of multiple age-associated diseases. Cyclic GMP-AMP synthase (cGAS) contributes to inflammaging by responding to endogenously-derived cytoplasmic DNA in aged cells. Although cGAS-knockout (KO) mice are viable, their aging has not been characterized. Unexpectedly, we found that cGAS KO mice exhibit an accelerated-aging phenotype, with induction of inflammation in multiple organs. cGAS KO mice display shortened median lifespan and increased frailty relative to wild-type mice. They show increased transcription of long interspersed nuclear element 1 (LINE1) retrotransposons, decreased DNA methylation on LINE1 elements and high levels of cytoplasmic LINE1 complementary DNA, which triggers inflammation, and this phenotype is recapitulated by cGAS knockdown in vitro. Furthermore, cells from cGAS KO mice show a smoothed H3K9me3 chromatin landscape and increased chromatin accessibility. In summary, our results show that cGAS functions to maintain heterochromatin organization in the nucleus, independent of its cytoplasmic role as a DNA sensor or its catalytic activity, with implications for geroprotective strategies targeting this pathway.

DOI: https://doi.org/10.1038/s43587-026-01206-y
Muscles. 2026 Aug 03. pii: 55. [Epub ahead of print]5(3):

Skeletal Muscle Dysfunction and Exercise Intolerance in COPD and Idiopathic Pulmonary Fibrosis: Extracellular Vesicles as Candidate Mediators of a Lung-Muscle Axis.

Georgios I Barkas, Zoe Daniil, Ourania S Kotsiou.

  Skeletal muscle dysfunction and exercise intolerance are major extrapulmonary manifestations of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), yet their severity is not fully predicted by pulmonary impairment. This narrative review examines extracellular vesicles (EVs) as candidate mediators of lung-muscle communication within a broader network of inflammatory, metabolic, vascular, nutritional, and inactivity-related mechanisms. The evidence is asymmetrical. COPD provides direct human skeletal muscle evidence for quadriceps microRNA dysregulation, impaired protein synthesis and mitochondrial function, oxidative stress, and abnormalities of the regenerative microvascular niche; however, none of these observations demonstrates delivery of pathogenic cargo from the lung by EVs. In IPF, EV-mediated epithelial-mesenchymal signalling, fibroblast activation, and profibrotic remodelling are well supported within the lung, whereas skeletal muscle effects remain indirect. Accordingly, the lung-muscle EV axis should be viewed as a biologically plausible, evidence-weighted hypothesis rather than an established causal pathway. Progress will require experiments that identify the cellular source of EVs, trace their vascular transit and skeletal muscle uptake, and demonstrate functional cargo transfer using EV-depletion, rescue, and integrated muscle readouts. Conventional size and morphology measurements do not reliably distinguish muscle- from lung-derived EVs; source discrimination currently depends more on molecular cargo and cell-associated markers. Hypoxia and transient or sustained oxygen desaturation may modify EV release and cargo through HIF- and redox-sensitive signalling, but disease-specific evidence connecting these changes to lung-to-muscle transfer in COPD or IPF remains limited.

Keywords:  COPD; exercise intolerance; extracellular vesicles; idiopathic pulmonary fibrosis; inter-organ communication; muscle wasting; skeletal muscle dysfunction; small extracellular vesicles

DOI:  https://doi.org/10.3390/muscles5030055
Cell Rep. 2026 Aug 24. pii: S2211-1247(26)00948-4. [Epub ahead of print]45(9): 117870

Zinc increases stress granule formation by promoting RNA condensation.

Luisa Macedo de Vasconcelos, Nina Ripin, Roy Parker.

  During cellular stress, mRNAs are condensed into stress granules through the action of G3BP1 and G3BP2. How intracellular conditions affect RNA-protein condensation in stress granules is still unclear. Herein, we present several observations that cells modulate intracellular zinc concentrations to reduce the direct impact of zinc on RNA condensation. We show that oxidative stress increases the intracellular labile zinc and the expression of zinc-sequestering proteins, metallothioneins. Increased intracellular zinc leads to increased stress granule formation and delays stress granule disassembly without increasing translational repression, while zinc depletion decreases stress granule formation, demonstrating that even endogenous levels of free zinc can affect granules. Mechanistically, we demonstrate how zinc promotes stress granule formation by directly stimulating RNA condensation interactions at 100× lower concentrations than magnesium. Together, these data indicate that zinc modulates RNA condensation and stress granule formation and implies an unappreciated potential role for zinc in modulating intracellular RNA structures and interactions.

Keywords:  CP: cell biology; CP: molecular biology; RNA condensation; oxidative stress; stress granules; zinc

DOI:  https://doi.org/10.1016/j.celrep.2026.117870
Life Metab. 2026 Oct;5(5): loag021

Stable clocks, rewired rhythms: circadian remodeling in skeletal muscle during aging, cachexia, and type 2 diabetes.

Francielly Morena, Mark R Viggars, Natalie Bohmke, Theodore E Ewachiw, Karyn A Esser.

  In mammals, nearly every cell contains an intrinsic circadian clock that functions both as a timekeeping system and an environmental sensor, integrating external cues to maintain alignment between internal physiology and the external environment. While the core clock machinery is broadly conserved across tissues, its downstream rhythmic gene programs are highly tissue-specific and essential for maintaining cellular and physiological homeostasis. In the skeletal muscle, rhythmic program dysregulation has emerged as a common denominator in many unfavorable conditions. However, high-resolution circadian time-course studies in the muscle remain limited. In this review, we examine current evidence on the behavior of the skeletal muscle molecular clock and rhythmic transcriptional programs across aging, cancer-induced muscle atrophy (cachexia), and type 2 diabetes (T2D). Despite distinct pathological contexts, all three conditions undergo substantial condition-specific remodeling of the muscle rhythmic gene program, often converging on biological processes such as lipid metabolism and chromatin regulation. Collectively, available data suggest that circadian dysfunction in these conditions arises not from collapse of the core molecular oscillator but from progressive rewiring of rhythmic transcriptional programs despite relative preservation of core clock integrity. We discuss emerging mechanisms-including metabolic remodeling, glucocorticoid signaling, chromatin regulation, and noncanonical clock regulators-that may underlie this process. Moving forward, multi-omics studies integrating transcriptomic, proteomic, metabolomic, and epigenomic time-series analyses will be essential to distinguish mechanisms responsible for condition-specific rhythmic gene regulation. A clearer understanding of how rhythmic gene programs are rewired may reveal new opportunities to restore temporal coordination and improve skeletal muscle health across diverse pathological conditions.

Keywords:  atrophy; circadian; muscle; rhythmic gene expression; sarcopenia

DOI:  https://doi.org/10.1093/lifemeta/loag021
Mol Ther Nucleic Acids. 2026 Sep 08. 37(3): 103022

Codon-optimized Npc1 mRNA corrects Niemann-Pick type C1 disease phenotypes in vitro and in vivo.

Ellen R Koufer, Alice Townsend, Youngseo Na, Adele B Correia, Noah K Latham, Koralege C Pathmasiri, Olga Ilnytska, Judith Storch, Kyle A Sullivan, Troy Halseth, Thaddeus J Kunkel, Elizabeth S Phillippi, Matthew L Lieberman, Stephanie M Cologna, Andrew P Lieberman, Daniel A Jacobson, Anna S Schwendeman, Mark L Schultz.

  Niemann-Pick type C1 disease is a lysosomal storage disorder caused by mutations in the NPC1 gene, resulting in the accumulation of unesterified cholesterol in multiple tissues. Despite its severity, therapeutic options remain limited. Using codon-optimized Npc1 mRNA delivered by lipid nanoparticles (Co-Npc1:LNPs), we achieved enhanced NPC1 protein expression and prolonged therapeutic activity in vitro, correcting both primary and secondary disease defects. In an Npc1 -/- mouse model, a single intravenous injection of Co-Npc1:LNP restored hepatic NPC1 protein levels, normalized autophagic flux, improved lipid abnormalities, and altered markers of liver injury. To interpret transcriptional changes post-Co-Npc1:LNP administration, we performed bulk RNA sequencing and applied MENTOR, a network-based clustering algorithm, and MENTOR-IA, an unbiased functional annotation tool. We identified transcriptionally restored pathways including cholesterol metabolism, lysosomal and mitochondrial function, and liver homeostasis. Overall, the Npc1 -/- mouse liver showed a transcriptional shift toward a more Npc1 +/+ state post-Co-Npc1:LNP treatment. Integration of single-nucleus RNA sequencing with bulk transcriptomics further revealed cell-type-specific correction of disease-associated gene expression across disease-relevant hepatic cell types. Together, we report the development and in vivo validation of the first mRNA-based therapeutic for Niemann-Pick type C1 disease.

Keywords:  MT: RNA/DNA editing; NPC1; Niemann-Pick type C1; Niemann-Pick type C1 liver; lipid nanoparticle; lysosomal storage disorder; mRNA therapy

DOI:  https://doi.org/10.1016/j.omtn.2026.103022