bims-musmir 2026-06-28 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–06–28
eleven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Nicotinamide Riboside Supplementation Protects Against Heat-Induced Skeletal Muscle Injury in Female Mice.
miR-339-5p impairs myogenic proliferation and differentiation by repressing contractile gene programs in skeletal muscle.
Estrogen-related receptor signaling counters sarcopenia and preserves exercise fitness in naturally aged mice.
An emergent disease-associated motor neuron state precedes cell death in ALS.
Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6.
VMA21 deficiency leads to autophagic dysregulation and altered vesicle trafficking in X-linked myopathy with excessive autophagy.
Sarcopenia and satellite cell homeostasis disruption: the dual function of NAD+ metabolism.
Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.
Development of a rapid and simple Xeno Nucleic Acid (XNA) sensor-based microRNA detection platform for Parkinson's disease diagnostics.
CIRBP maintains skeletal muscle mitochondrial energy homeostasis via mt-ATP6 to ameliorate sarcopenia.
An immunological panacea for cancer-related cachexia.

Muscles. 2026 Jun 15. pii: 44. [Epub ahead of print]5(2):

Nicotinamide Riboside Supplementation Protects Against Heat-Induced Skeletal Muscle Injury in Female Mice.

Yifan Chen, Tianzheng Yu.

  Micronutrients are essential for optimal muscle metabolic function. We previously showed that heat-induced skeletal muscle injury is associated with depletion of nicotinamide adenine dinucleotide (NAD+) and magnesium (Mg2+), and boosting NAD+ abundance with the precursor nicotinamide riboside (NR) improves skeletal muscle integrity against heat stress in male mice. In this study, we hypothesized that NR supplementation would prevent heat-induced skeletal muscle injury in female mice. Female 6-week-old C57BL/6J mice were orally administered vehicle or NR (185 mg/kg body weight) daily for 10 days. Subsequently, they underwent a single sham or heat exposure experiment. No significant differences in muscle NAD+ content were observed between vehicle and NR groups or between sham and heat groups. Heat groups showed significantly lower muscle Mg2+ levels compared to sham groups. In vehicle groups, heat exposure caused significant inflammation, oxidative stress, mitochondrial impairment, and apoptosis in skeletal muscle compared to the sham condition. NR treatment significantly reduced these alterations. While neither heat exposure nor NR affected muscle NAD+ homeostasis, the protective effects of NR on skeletal muscle against heat stress were similar to those observed in male mice. Together, our results demonstrate the preventive effect of NR on muscle heat injury in female mice. This effect is associated with anti-inflammatory and antioxidative activities, mitochondrial protection, and anti-apoptosis without NAD+ homeostatic alterations.

Keywords:  ATP; gender; heat stress; hyperthermia; niacin; skeletal muscle

DOI:  https://doi.org/10.3390/muscles5020044
Am J Physiol Cell Physiol. 2026 Jun 26.

miR-339-5p impairs myogenic proliferation and differentiation by repressing contractile gene programs in skeletal muscle.

Xue Yu, Elena Caria, Dimitrius Santiago P S F Guimarães, Maxence Jollet, David Rizo-Roca, Alesandra A Marica, Souren Mkrtchian, Marta Gómez-Galán, Anna Krook, Nicolas J Pillon.

  MicroRNAs (miRNAs) are critical regulators of skeletal muscle development and adaptation, orchestrating the balance between proliferation, differentiation, and tissue repair. Here, we identify miR-339-5p as a previously unrecognized, conserved regulator of skeletal muscle remodeling. Transcriptomic analysis from human, mouse, and rat studies revealed that miR-339-5p is consistently upregulated in skeletal muscle under conditions of stress or injury and declines during myogenic differentiation in vitro. Gain-of-function experiments demonstrated that miR-339-5p overexpression impairs expression of genes associated with myogenic differentiation and promotes expression of proliferative markers in both primary human myotubes and mouse C2C12 cells. Transcriptomic profiling confirmed widespread repression of pathways involved in cytoskeletal organization, myofibrillar assembly, and mitochondrial function. In vivo, electroporation-mediated overexpression of miR-339-5p in mouse tibialis anterior altered regeneration-associated gene expression and increased the number of immature fibers, therefore modulating tissue remodeling during post-injury growth. Integrated analyses combining target prediction algorithms, differentiation-associated correlations, and overexpression datasets identified seven conserved high-confidence miR-339-5p targets, among which the autophagy-associated phosphatase MTMR3 emerged as the most consistently regulated candidate. Collectively, our data demonstrate that miR-339-5p functions as a conserved inhibitor of myogenic progression, linking injury-induced stress responses to delayed differentiation and altered muscle remodeling. These findings establish miR-339-5p as a potential therapeutic target in conditions characterized by impaired muscle regeneration or dysregulated tissue remodeling.

Keywords:  microRNA; myogenesis; skeletal muscle; tissue remodeling

DOI:  https://doi.org/10.1152/ajpcell.00898.2025
bioRxiv. 2026 Jun 11. pii: 2026.06.07.730739. [Epub ahead of print]

Estrogen-related receptor signaling counters sarcopenia and preserves exercise fitness in naturally aged mice.

D H Sopariwala, A DeBruine, S Poliakova, E Mosa, E Mann, Citu Citu, Zhongming Zhao, A Kumar, V A Narkar.

Background: Estrogen-related receptor gamma (ERRγ) drives an exercise mimicking aerobic gene program in the skeletal muscle that could be beneficial in aging. We have investigated the effect of chronic ERRγ activation on minimizing sarcopenia.
Methods: Experiments were performed in muscle specific ERRγ transgenic (TG) mice and wild type (WT) littermates, at young (4-5 months) and old (24-26 months) age. In the skeletal muscle, global gene expression changes, as well as myofiber histological changes in fiber type, size, vascular supply and neuromuscular junction (NMJ), and mitochondrial content were measured. Functional analysis was performed using in vivo muscle contraction assay. Exercise fitness was measured using treadmill sprint and endurance test. Gene and protein expression was measured using QPCR and Westerns, respectively.
Results: ERRγ activates a pan-ERR aerobic program in the skeletal muscle to increase expression of 574 genes including ERRα, mitochondrial homeostasis (e.g. Mfn1, Opa1, Drp1, Fis1, and Tfam), vascularization (e.g. Vegfa, Angpt1, Fgf1), and neuromuscular junction (NMJ) (e.g. Nrp1, Aspa, Ptprm, Cxcr4), simultaneously suppressing the expression of atrophy related genes (e.g. Atrogin1, Traf6, Nedd4, Myd88, p21). ERRγ increases mitochondrial content [Mitochondrial area: old TG vs. WT, 2.00 fold; young TG vs. WT, 1.32 fold], oxidative capacity [NADH-TR activity: old TG vs. WT, 1.20 fold; young TG vs. WT, 1.22 fold] and myofiber type [2a: old TG (687±258) vs. WT (252±71); young TG (797±168) vs. WT (440±76); 2x: old TG 1348±87 vs. WT 976±219; young TG 1131±135 vs. WT 936±84; 2b: old TG (798±103) vs. WT (1628±148); young TG (967±133) vs. WT (1623±189)], and capillarity [capillary-to-myofiber ratio: old TG (3.25±0.19) vs. WT (2.41±0.16); young TG (3.41±0.21) vs WT (2.59±0.2)] and [NMJ number [old TG (67±8) vs. WT (40±9); young TG (77±11) vs WT (77±7)], mitigating age-related loss of NMJ and myofiber cross-sectional area [old TG (1570±147µm 2) vs. WT (1692.5±208µm 2 ) WT; young TG (1828.15±132.8µm 2 ) vs. WT (2109.7±296.8µm 2 )]. ERRγ overexpression preserves muscle contractility with aging [Fatigue resistance: 22.72% reduction in force in old vs. young WT; 3.11% reduction in force between old vs. young TG]. Furthermore, ERRγ maintains exercise fitness in old mice [Running: old TG (2964.52±405m) vs. old WT (910.75±6034m); young TG (2232.43±193.64m) vs. young WT (1366.76±60.76m)].
Conclusions: ERRγ drives a pan-ERR and counter sarcopenic gene program enhancing oxidative myofiber type, mitochondrial content, vasculature, and NMJ in aging muscle. Consequently, ERRγ minimizes myofiber atrophy, preserves contractility, and improves exercise fitness in old mice. Therefore, ERRs are potential translational targets for combating sarcopenia.

DOI: https://doi.org/10.64898/2026.06.07.730739
Cell. 2026 Jun 23. pii: S0092-8674(26)00647-1. [Epub ahead of print]

An emergent disease-associated motor neuron state precedes cell death in ALS.

Olivia Gautier, Jacob A Blum, Thao P Nguyen, Shaolong Cao, Sandy Klemm, Mai Yamakawa, Dann Huh, Jessica A Hurt, Nasa Sinnott-Armstrong, Yi Zeng, Chung-Ha O Davis, Juliane Bombosch, Chang Liu, Lisa N Encarnacion, Kevin A Guttenplan, Derek Chen, Arwa Kathiria, Luke Zhao, Stephen Moore, Alex Meng, Kailee Ong, Don W Cleveland, John Ravits, Jessica E Rexach, William J Greenleaf, Aaron D Gitler.

  To define molecular determinants of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons together with spatial transcriptomics from the SOD1-G93A mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a distinct cell state we named "disease-associated motor neurons" (DMs). We identified transcription factor networks that govern how healthy cells transition into DMs and those associated with motor neuron subtype-selective vulnerability. Upregulation of DM-associated transcription factors in human motor neurons induced key features of DMs, demonstrating an active regulatory component. Human ALS spinal cord single-nucleus RNA sequencing data demonstrated conservation of the DM signature in alpha motor neurons, and human orthologs of regions differentially accessible in SOD1-G93A mouse motor neurons were enriched for ALS genetic risk variants. Together, these findings establish a conserved, genetically linked motor neuron signature in ALS.

Keywords:  ALS; cell states; microglial activation; motor neuron; neurodegeneration; selective vulnerability; snATAC-seq; snRNA-seq; spatial transcriptomics; spinal cord

DOI:  https://doi.org/10.1016/j.cell.2026.05.047
Hum Mol Genet. 2026 Jun 12. pii: ddag023. [Epub ahead of print]35(12):

Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6.

Rianne J Baelde, Leander A Vonk, Edgar E Nollet, Ricardo A Galli, Alexcia Fortes Monteiro, Sultan Bastu, Bornale Das, Michel van Weeghel, Bauke V Schomakers, Kasper T Vinten, Marloes van den Berg, Jolanda van der Velden, Riekelt H Houtkooper, Nicol C Voermans, Edoardo Malfatti, Coen A C Ottenheijm, Josine M de Winter.

  Nemaline Myopathy type 6 (NEM6) is a congenital myopathy caused by variants in Kelch-repeat-and-BTB-(POZ)-Domain-Containing-13 (KBTBD13). The majority of the NEM6 patients harbor the Dutch founding variant KBTBD13R408C (c.1222C > T, p.Arg408Cys) and experience skeletal muscle weakness and sarcomere-based hypercontractility. Histological characterization of NEM6 patient biopsies by NADH staining shows the presence of cores, suggesting mitochondrial dysfunction. We aimed to elucidate the role of mitochondrial dysfunction in NEM6 pathology and tested the ability of the NAD+ precursor nicotinamide riboside (NR) to improve mitochondrial performance. We performed a natural history study in homozygous Kbtbd13R408C-knockin mice (NEM6 mouse model) to investigate the onset and progression of mitochondrial dysfunction in NEM6. We performed high-resolution respirometry, metabolic treadmill experiments and histoenzymatic NADH and SDH stainings on cryosections. Additionally, we used multi-omics analyses to investigate impacted pathways and metabolite dysregulation and performed NR supplementation for eight weeks to prevent the onset of mitochondrial dysfunction in NEM6 mice. Throughout disease progression, NEM6 mice display decreased mitochondrial respiration, impaired metabolic performance and the presence of cores with histoenzymatic reactions. Multi-omics studies revealed that the TCA cycle is heavily impacted and that NAD+ levels are decreased throughout disease progression. We aimed to restore NAD+ levels by supplementation of NR. Remarkably, NR treatment in 1-months-old NEM6 mice, prevented the onset of mitochondrial dysfunction. In conclusion, these results provide insight in the onset and progression of mitochondrial dysfunction in NEM6 and offer proof-of-concept for NR as a therapeutic strategy.

Keywords:  Congenital myopathy; Mitochondria; NAD+ metabolism; Nemaline myopathy; Skeletal muscle

DOI:  https://doi.org/10.1093/hmg/ddag023
Acta Neuropathol. 2026 Jun 26. pii: 73. [Epub ahead of print]151(1):

VMA21 deficiency leads to autophagic dysregulation and altered vesicle trafficking in X-linked myopathy with excessive autophagy.

Christian A Suarez, Sara K Pittman, Michio Inoue, Eileen M Lynch, Andrew Moran, Angèle N Merlet, Emmanuelle Lacenne, Teresinha Evangelista, Conrad C Weihl.

  X-Linked myopathy with excessive autophagy (XMEA) is a rare vacuolar myopathy caused by mutations in Vma21, an assembly chaperone required for vacuolar H⁺-ATPase (V-ATPase) function. However, the mechanisms linking Vma21 deficiency to progressive muscle pathology remain poorly understood, in part due to the lack of suitable animal models. To address this gap, we generated conditional Vma21 knockout mouse models to investigate the consequences of Vma21 loss in striated muscle. Combined deletion of Vma21 in skeletal and cardiac muscle resulted in early lethality driven by severe cardiomyopathy associated with autophagic dysregulation, preceding the development of skeletal muscle pathology. In contrast, inducible skeletal muscle-specific deletion of Vma21 produced progressive muscle weakness and myopathy characterized by centralized nuclei, fiber splitting, and increased fiber size variability. Affected skeletal muscle also recapitulated defining pathological hallmarks of XMEA, including basal lamina reduplication and autophagic vacuoles with sarcolemmal features (AVSFs). Ultrastructural analysis revealed membrane-bound vacuoles containing partially undegraded material that frequently accumulated at the subsarcolemmal region, together with clusters of vesicular structures. Notably, mutant muscle exhibited increased staining for the late endosomal/exosomal marker CD63, which strongly colocalized with the complement membrane attack complex C5b-9. A similar increase in CD63 staining and its colocalization with C5b-9 were observed in skeletal muscle biopsies from patients with XMEA. Together, these models faithfully recapitulate key pathological features of XMEA and identify the accumulation of CD63-positive structures and their colocalization with C5b-9 as previously unrecognized features of Vma21-deficient skeletal muscle, implicating altered vesicle trafficking in XMEA pathogenesis.

Keywords:  Autophagy; Membrane attack complex; VMA21; Vacuolar myopathy; Vesicle trafficking; XMEA

DOI:  https://doi.org/10.1007/s00401-026-03044-z
Front Nutr. 2026 ;13 1803560

Sarcopenia and satellite cell homeostasis disruption: the dual function of NAD+ metabolism.

Chenyuan Li, Yue Ai, Jieni Yan, Shuhua Wu.

  Sarcopenia is an age-related syndrome characterized by progressive loss of skeletal muscle mass and function, which is closely associated with impaired regenerative capacity of muscle satellite cells (MuSCs). During aging, the MuSC niche undergoes severe deterioration, including mitochondrial dysfunction, chronic inflammation, and neuromuscular junction (NMJ) degeneration, all of which compromise MuSC quiescence, proliferation, and differentiation. Nicotinamide adenine dinucleotide (NAD+) serves as a critical coenzyme and signaling molecule that governs MuSC homeostasis in a context-dependent, dual-function manner. Moderate NAD+ repletion via precursors such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) activates SIRT1 and SIRT3, enhances mitochondrial bioenergetics, reduces oxidative stress, and promotes MuSC proliferation and myogenic differentiation. In contrast, under pathological or aging conditions, excessive or dysregulated NAD+ signaling activates SIRT2 to deacetylate PAX7 and repress Myogenic Differentiation 1 (MyoD), leading to cell-cycle arrest and MuSC exhaustion. This review adopts a hypothesis-driven framework to systematically summarize the molecular crosstalk between NAD+ metabolism, sirtuin family deacetylases (SIRTs), and MuSC fate regulation. We integrate evidence from nearly 60 representative preclinical and clinical studies, clarify the dual-function role of NAD+, and address current inconsistencies in the field. We also highlight key limitations and propose future directions for developing NAD+-targeted therapies for sarcopenia.

Keywords:  MuSC homeostasis; NAD+; sarcopenia; satellite cell; sirtuins

DOI:  https://doi.org/10.3389/fnut.2026.1803560
Cell Rep. 2026 Jun 26. pii: S2211-1247(26)00685-6. [Epub ahead of print]45(7): 117607

Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.

Tatsuki Yasuda, Aoi Ichikawa, Kenta Onoue, Emi Ogasawara, Takaya Ishihara, Hidetaka Kosako, Naotada Ishihara.

  Mitochondria are dynamic organelles that continuously remodel their morphology through fusion and fission in response to cellular cues. While this dynamic behavior is essential for diverse cellular functions, how mitochondrial dynamics influence innate immune responses remains incompletely understood. Here, we show that mitochondrial hyperfusion-induced by loss of the fission factor DRP1 or by cellular stress, including cycloheximide or doxorubicin treatment-is associated with activation of a RIG-I-MAVS-dependent innate immune response and BAX-dependent cytosolic release of mitochondrial RNA. Functionally, our data suggest that this pathway contributes to enhanced susceptibility to NK cell-mediated cytotoxicity in vitro and reduced tumor growth in a xenograft model. Collectively, our findings identify mitochondrial hyperfusion-induced mtRNA release as a mechanism that engages innate immune signaling downstream of impaired mitochondrial dynamics.

Keywords:  CP: immunology; DRP1; RIG-I; innate immunity; mitochondrial RNA; mitochondrial dynamics; mitochondrial hyperfusion; molecular biology

DOI:  https://doi.org/10.1016/j.celrep.2026.117607
J Nanobiotechnology. 2026 Jun 23.

Development of a rapid and simple Xeno Nucleic Acid (XNA) sensor-based microRNA detection platform for Parkinson's disease diagnostics.

Mi Young Byun, Moon Young Ryu, Seok Jong Chung, Bora Lee, Jong Ryeol Oh, Jin Kyu Woo, Jin Young Shin, Min Kyun Han, Oh Young Bang, Yun Joong Kim, Ming-Che Kuo, Hsiang-Hsuan Lin-Wang, Rudy-Meei Wu, Shau-Ping Lin, Seok Keun Cho, Phil Hyu Lee, Seong Wook Yang.

  Current biomarkers for Parkinson's disease (PD) diagnosis, including imaging tracers, α-synuclein seeding assays, proteomic markers, and metabolomic signatures, are often limited by invasiveness, cost, scalability, or insufficient reproducibility. Circulating microRNAs (miRNAs) are attractive minimally invasive biomarkers because they are mechanistically linked to disease-associated pathways and remain stable in biofluids. However, the clinical translation of miRNA biomarkers has been hindered by multistep workflows and analytical variability arising from adapter ligation, reverse transcription, amplification drift, and cross-platform inconsistency in qRT-PCR, sequencing, and hybridization-based assays. To address these limitations, we developed XENO-Q, a rapid three-step platform that enables bias-minimized miRNA quantification through target-selective synthesis, in which only sensor-confirmed miRNAs are converted into amplifiable chimera products. XENO-Q enables linear quantification across several orders of magnitude with femtomolar sensitivity and high reproducibility while maintaining compatibility with qRT-PCR, ddPCR, and nanopore sequencing workflows. As a demonstration of clinical applicability, XENO-Q identified a two-marker circulating miRNA signature that accurately distinguished PD from other neurodegenerative conditions. These findings establish XENO-Q as a scalable and clinically translatable framework for next-generation miRNA diagnostics beyond Parkinson's disease.

Keywords:  Bias-minimized quantification; Blood biomarker; MicroRNA (miRNA); Molecular diagnostics; Parkinson's disease; XENO-Q

DOI:  https://doi.org/10.1186/s12951-026-04707-5
Biochem Biophys Res Commun. 2026 Jun 20. pii: S0006-291X(26)00947-2. [Epub ahead of print]829 154183

CIRBP maintains skeletal muscle mitochondrial energy homeostasis via mt-ATP6 to ameliorate sarcopenia.

Zhouyi Wang, Yang Guo, Zhen Hu, Hongyong Zhang, Qingmei Liu.

  Sarcopenia, characterized by progressive loss of skeletal muscle mass and function, represents a major public health challenge in aging societies; its underlying molecular mechanisms remain incompletely understood, and no approved disease-specific pharmacotherapy exists. Here, we demonstrate that CIRBP is essential for skeletal muscle homeostatic maintenance during aging. Eighteen-month-old Cirbp-/- mice exhibited a canonical sarcopenic phenotype-reduced compound muscle action potential amplitude, decreased grip strength, accelerated fatigue, and prominent myofiber atrophy-accompanied by coordinate upregulation of the ubiquitin-proteasome effectors Atrogin-1, MuRF1, and Myostatin. Whole-transcriptome RNA sequencing identified 814 differentially expressed genes, predominantly downregulated, among which mt-Atp6-encoding mitochondrial ATP synthase subunit 6-exhibited the most pronounced reduction in absolute expression. CIRBP deficiency led to coordinate downregulation of Atp6 mRNA and ATP6 protein, accompanied by severe mitochondrial cristae disruption and oxidative phosphorylation dysfunction, collectively producing chronic energy insufficiency that drove protein degradation pathway activation and progressive myofiber atrophy. Conversely, AAV-mediated CIRBP overexpression simultaneously upregulated ATP6 expression, suppressed protein degradation pathway activation, and substantially improved skeletal muscle function in aged mice at both electrophysiological and mechanical levels. This study establishes the CIRBP-Atp6 mRNA-mitochondrial energy metabolism regulatory axis as a central node in skeletal muscle aging homeostasis, providing a new mechanistic framework and potential therapeutic targets for sarcopenia intervention.

Keywords:  Cold-inducible RNA-Binding protein; Mitochondrial ATP synthase subunit 6; Mitochondrial dysfunction; Sarcopenia; Skeletal muscle aging

DOI:  https://doi.org/10.1016/j.bbrc.2026.154183
Trends Cancer. 2026 Jun 24. pii: S2405-8033(26)00133-0. [Epub ahead of print]

An immunological panacea for cancer-related cachexia.

Jingyu Xue, Tianyi Lu, Kailin Yang, Alexander Birbrair, Shengtao Zhou.

  Cancer cachexia, responsible for up to 30% of cancer deaths, has transitioned conceptually from a mere nutritional deficit into a highly coordinated, multi-organ immunometabolic network that systematically dismantles host homeostasis. This review synthesizes the paradigm-shifting discoveries that position the immune system as the central conductor of tissue wasting. We delineate how redundant inflammatory cascades, neuro-immune circuits, and local cellular plasticity converge to drive muscle and adipose catabolism. Furthermore, we dissect the metabolic competition for nutrients between tumor cells and host immunity, which accelerates structural degradation. Finally, we highlight how single-cell multiomics, spatial transcriptomics, and artificial intelligence are redefining clinical stratification, shifting the therapeutic horizon toward individualized, multi-node immunometabolic interventions, thereby providing a theoretical framework for the management of cachectic wasting syndrome.

Keywords:  cachexia; cytokines; immune cells; immune metabolism

DOI:  https://doi.org/10.1016/j.trecan.2026.06.005