bims-musmir Biomed News
on microRNAs in muscle
Issue of 2026–09–13
twelve papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. Spatiotemporal Multi-Omic Mapping Reveals Liver-Muscle Metabolic Crosstalk in Cancer Cachexia.
  2. Dysregulated microRNA-mRNA networks in SOD1G93A mouse skeletal muscle reveal metabolic impairments in ALS.
  3. Nerve injury-induced protein 2 preserves lysosomal membrane integrity to suppress ferroptosis.
  4. miR-191 affects skeletal muscle differentiation by regulating Wwp1 in mouse myoblasts.
  5. Hypoxia-inducible factor-1a (HIF1a) as a context-dependent integrator of metabolic stress in skeletal muscle.
  6. MAFF is a transcription factor that regulates contraction-induced skeletal muscle transcription.
  7. Multi-Omics Analysis Reveals That Aβ42- Me3 Co-Aggregation Induces Mitophagy Blockade in Early Stages of Alzheimer's Disease.
  8. Mitochondrial Proteostasis Links Diabetes and Sarcopenia: Cross-Scale Convergence from Experimental Models to Human Multi-Omics.
  9. Hemifusomes and proteolipid nanodroplets: a critical synthesis of an emerging model for endosomal membrane remodeling.
  10. Oxidative stress triggers RNAPII arrest through PARylation and DNA damage.
  11. R17 Drives Heparan Sulfate Clearance via Endolysosomal Trafficking.
  12. Mitochondrial immunometabolism in sepsis: bridging immune cell dysfunction and organ failure.
  1. Adv Sci (Weinh). 2026 Sep 08. e77489
    Spatiotemporal Multi-Omic Mapping Reveals Liver-Muscle Metabolic Crosstalk in Cancer Cachexia.
    Zihan Tian, Qianyu Wang, Wenyan Gao, Xianfeng Li, Jiawen Fan, Xiaoliang Wu, Siqi Liu, Xiangdong Ming, Danna Yeerken, Mutian Shen, Qingjie Min, Qimin Zhan, Yan Wang.
      Tumor and host interaction contributes to cancer cachexia, a systemic wasting syndrome characterized by tissue loss (adipose and skeletal muscle), anorexia, fatigue, and metabolic reprogramming. Nevertheless, the spatio-temporal molecular dynamics of multiple tissues during cancer cachexia development remain elusive. Here, we present a comprehensive overview of the biological alterations and metabolic reprogramming of cancer cachexia across two species, 25 organs, and 3230 samples, by integrating transcriptomic, proteomic, and metabolomic profiles spanning different cachectic stages and sexual dimorphism. Using this cancer cachexia atlas (CCAtlas), we identified dysregulated tissues of cancer cachexia, including skeletal muscle, liver, and blood. We revealed coordinated metabolic reprogramming across tissues, including dysregulated amino acid metabolism and one-carbon metabolism. Temporal profiling illustrated dynamic molecular signatures during cancer cachexia progression. The exacerbated inflammatory status in males potentially contributed to a more severe whole-body wasting phenotype. The liver-muscle crosstalk potentiated skeletal muscle atrophy through creatine deficiency via hepatic Gamt downregulation in the LLC model. Creatine supplementation and hepatic Gamt overexpression in the LLC model attenuated skeletal muscle wasting. Together, CCAtlas provides fundamental and systemic insights into multi-omic molecular dynamics and metabolic rewiring of cancer cachexia from the perspective of tumor and/or inter-organ crosstalk across species.
    Keywords:  Gamt; cancer cachexia; creatine; inter‐organ crosstalk; metabolism reprogramming; spatiotemporal dynamics
    DOI:  https://doi.org/10.1002/advs.77489
  2. Dis Model Mech. 2026 Sep 10. pii: dmm.052963. [Epub ahead of print]
    Dysregulated microRNA-mRNA networks in SOD1G93A mouse skeletal muscle reveal metabolic impairments in ALS.
    Libby Moody, Eleni Christoforidou, Greig Joilin, Andrew Dilley, Majid Hafezparast.
      Amyotrophic lateral sclerosis (ALS) is a multi-system disease in which skeletal muscle actively contributes to pathology, yet the regulatory circuits that drive muscle dysfunction remain unclear. We examined microRNA (miRNA)-messenger RNA (mRNA) interactions in the gastrocnemius of hSOD1G93A mice across presymptomatic, early- and late-symptomatic stages, using RNA-seq, bioinformatics, and RT-qPCR. Compared with hSOD1WT and non-transgenic controls, hSOD1G93A muscle showed mutation-specific transcriptome reprogramming: 48 dysregulated miRNAs and 558 mRNAs at presymptomatic, and 64 miRNAs and 685 mRNAs at late-symptomatic stages. Functional enrichment pinpointed carbohydrate-handling pathways (glycolysis/gluconeogenesis, pentose-phosphate, fructose-mannose metabolism) as the dominant downregulated gene sets. Network analysis revealed clusters in which upregulated miRNAs converged on, and showed inverse expression patterns relative to metabolic transcripts. RT-qPCR confirmed inverse expression of 10 candidate miRNAs and 11 metabolic mRNAs, substantiating miRNA-guided repression of glycolytic enzymes and energy-sensing nodes. Collectively, we show that SOD1G93A drives an early, sustained miRNA signature that dampens glycolysis gene expression, which could promote the fast-to-slow fibre-type transition and exacerbate energy deficit in ALS muscle. Targeting these circuits offers a strategy to restore metabolic balance and slow disease progression.
    Keywords:  Amyotrophic Lateral Sclerosis; Metabolism; Motor Neurone Disease; Muscle; SOD1; microRNA
    DOI:  https://doi.org/10.1242/dmm.052963
  3. Elife. 2026 Sep 11. pii: RP110919. [Epub ahead of print]15
    Nerve injury-induced protein 2 preserves lysosomal membrane integrity to suppress ferroptosis.
    Jin Zhang, Miranda Bustamante, Yang Shi, Ken-Ichi Nakajima, Xinbin Chen.
      Nerve injury-induced protein 1 (NINJ1), a cell adhesion molecule, is oligomerized during lytic cell death and mediates plasma membrane rupture to release large intracellular molecules that propagate the inflammatory response. We and others previously showed that NINJ2, a close relative of NINJ1, does not promote plasma membrane rupture to spread inflammation. Here, we identify that NINJ2 is necessary for lysosome membrane integrity to protect cells from ferroptosis. Specifically, we found that NINJ2 localizes to lysosomes and interacts with LAMP1, an anchor glycoprotein of the lysosome membranes and a sensor of stressed lysosomes. We also found that loss of NINJ2 exacerbates lysosomal membrane permeabilization (LMP), which allows for selective leakage of lysosomal contents, such as labile iron, into the cytosol. Accordingly, loss of NINJ2 elevates cellular labile iron accumulation and decreases expression of ferritins, the primary intracellular iron storage protein complexes. Mechanistically, we found that loss of NINJ2 promotes ferritin FTH degradation in lysosomes, which can be reversed by knockdown of LAMP1. Moreover, we found that loss of NINJ2 sensitizes cells to ferroptosis induced by RSL3 and Erastin, consistent with a recent study that loss of NINJ2 predisposes mice to chronic inflammation. Together, these findings uncover a previously unrecognized activity of NINJ2 from lysosome homeostasis to ferroptosis, which can be explored as a cancer therapeutic strategy, especially considering that NINJ2 and ferritins are found to be overexpressed and positively associated with iron-addicted cancers.
    Keywords:  Lamp1; NINJ2; cancer biology; ferritin; ferroptosis; human; lysosomal membrane permeabilities
    DOI:  https://doi.org/10.7554/eLife.110919
  4. PLoS One. 2026 ;21(9): e0355370
    miR-191 affects skeletal muscle differentiation by regulating Wwp1 in mouse myoblasts.
    Wenhua Pu, Meimei Zhang, Siman Guo, Xiang Bao, Wenjia Cui, Chuncheng Liu.
      Skeletal muscle atrophy is a key complication of various diseases, such as chronic obstructive pulmonary disease (COPD) and cancer. The mechanisms by which these diseases affect skeletal muscle metabolism need to be deeply explored. By analyzing the miRNA expression profiles in the plasma of patients with COPD, we found that miR-191 expression was significantly altered and it may influence skeletal muscle metabolism by regulating ubiquitination and the mTOR pathway. Using a mouse model of skeletal muscle injury induced by cardiotoxin, we found that miR-191 and Wwp1 showed a dynamic negative correlation in injury repair. Transfection with miR-191 mimics significantly inhibited the expression of myogenic regulatory factor Myog and differentiation markers Myh1/7/8, while downregulating key genes in the mTOR pathway. Molecular mechanism studies showed that miR-191 could directly act on the 3' untranslated region of the Wwp1 gene to inhibit its expression. This study reveals the important role of the miR-191/Wwp1 axis in skeletal muscle differentiation and provides a novel theoretical basis for research on muscle atrophy induced by COPD, cancer cachexia, and other diseases.
    DOI:  https://doi.org/10.1371/journal.pone.0355370
  5. J Physiol. 2026 Sep 10.
    Hypoxia-inducible factor-1a (HIF1a) as a context-dependent integrator of metabolic stress in skeletal muscle.
    Nicole Welch, Pugazhendhi Kannan, Seshu Vardhan Pothabathula, Annette Bellar, Abhishek A Chakraborty, Saurabh Mishra, Srinivasan Dasarathy.
      Skeletal muscle experiences large fluctuations in ATP demand and redox state during contraction, ischaemia and chronic disease, requiring rapid adaptations in substrate selection, mitochondrial workload, vascular coupling, regeneration and protein homeostasis. Hypoxia-inducible factor-1a (HIF1a) is classically viewed as an oxygen-responsive transcription factor that mediates rapid adaptation to hypoxia. Accumulating evidence across tissues, including skeletal muscle, indicates that HIF1a is also responsive to physiological and pathological inputs, such as exercise, circadian timing, redox perturbations and endogenous/exogenous cytotoxins, even when tissue hypoxia is not detectable. During hypoxia, including transient mismatches between oxygen demand and supply during muscle contraction, HIF1a activation shifts metabolism from oxidative to non-oxidative energy production, suppresses non-essential energy-consuming processes, including protein homeostasis, and promotes vascular responses that improve oxygen delivery. Under normoxic conditions, persistent HIF1a activation promotes maladaptive responses, including impaired mitochondrial remodelling, reduced anabolic responsiveness, defective regeneration, fibrosis, and atrophy- and senescence-associated reprogramming. Current evidence shows that this shift from adaptive to maladaptive signalling is determined in part by post-translational mechanisms that regulate signalling duration and target gene engagement, as well as by fibre type, circadian state and the nature of the upstream stressor. Unlike the robust responses in muscle tissue observed in preclinical models, human muscle biopsies often show modest or transient HIF1a accumulation, yet transcriptional responses indicate meaningful pathway activation, suggesting that biologically relevant signalling occurs even when total protein levels appear low. Genetic models, multiomics, and human studies support HIF1a as a context-dependent regulator of metabolic reprogramming that balances short-term adaptation with long-term energetic cost.
    Keywords:  HIF1a; ammonia; context‐dependent; ethanol; hypoxia inducible factor‐1a; normoxia; skeletal muscle
    DOI:  https://doi.org/10.1113/JP291159
  6. Life Sci Alliance. 2026 Dec;pii: e202603709. [Epub ahead of print]9(12):
    MAFF is a transcription factor that regulates contraction-induced skeletal muscle transcription.
    Taku Fukushima, Taiju Fujioka, Satoru Masubuchi, Iori Sakakibara.
      Skeletal muscle adapts to exercise through rapid transcriptional remodeling, but regulators that link contractile activity to these gene programs remain unclear. Here we show that MAFF, a small MAF transcription factor, is consistently induced by acute exercise in both human and mouse skeletal muscle, with induction restricted to muscles recruited by the exercise modality. In C2C12 cells, Maff was induced by in vitro electrical pulse stimulation model. Using CRISPR/Cas9-mediated Maff knockout C2C12 cells, we found that loss of Maff reduced myogenic fusion with accumulation of unfused nuclei. RNA sequencing revealed broad reprogramming in Maff-deficient myotubes, including reduced expression of muscle structural and contractile genes and increased interferon/immune responses and extracellular matrix-related signatures. Moreover, Maff deficiency attenuated a subset of electrical pulse stimulation-responsive genes. Together, these data identify MAFF as a component of the transcriptional machinery supporting myogenic maturation and contraction-evoked gene regulation.
    DOI:  https://doi.org/10.26508/lsa.202603709
  7. MedComm (2020). 2026 Sep;7(9): e70984
    Multi-Omics Analysis Reveals That Aβ42- Me3 Co-Aggregation Induces Mitophagy Blockade in Early Stages of Alzheimer's Disease.
    Wenjie Zhu, Yuanyuan Zhang, Pengjie Li, Yingying Zhong, Yawei Lin, Xin Liu.
      Mitochondrial dysfunction is one of the earliest pathological features of Alzheimer's disease (AD), preceding overt neurodegeneration and cognitive decline. Amyloid-β (Aβ) accumulation has long been considered a central pathogenic event in AD, yet how Aβ toxicity is mechanistically linked to mitochondrial impairment during early disease stages remains incompletely understood. To address this, we combined multi-omics with in vivo and in vitro genetic interventions. Here, we show that malic enzyme 3 (Me3) links Aβ aggregation to mitochondrial dysfunction in APP/PS1 mice and neuronal cells. At ultra-early and early AD stages (3 and 6 months), Me3 was upregulated and accumulated within mitochondria, where it colocalized with Aβ42 and physically interacted with it, an association linked to oxidative stress and impaired mitophagy. Knockdown of Me3 reduced mitochondrial reactive oxygen species, improved mitochondrial morphology, and alleviated mitophagy defects in both cellular and mouse models, with statistical significance across these functional measurements (p < 0.05). These results suggest that Me3 functions not only as a metabolic responder to Aβ-associated stress but also as a contributor to early mitochondrial pathology. By identifying the Aβ-Me3 axis, this study provides mechanistic insight into early mitochondrial dysfunction in AD, while further validation in human AD samples remains necessary.
    Keywords:  Alzheimer's disease; malic enzyme 3; mitophagy; proteomics; β‐amyloid
    DOI:  https://doi.org/10.1002/mco2.70984
  8. Diabetes Metab J. 2026 Sep;50(5): 825-843
    Mitochondrial Proteostasis Links Diabetes and Sarcopenia: Cross-Scale Convergence from Experimental Models to Human Multi-Omics.
    Shibo Wei, Soyeon Shin, Dongryeol Ryu, Chang-Myung Oh.
      Sarcopenia in type 2 diabetes mellitus is increasingly recognized as a mechanistic consequence of chronic metabolic stress rather than mere age-related comorbidity. This review synthesizes evidence demonstrating how insulin resistance, hyperglycemia, lipotoxicity, and inflammation converge on skeletal muscle mitochondrial proteostasis to drive progressive decline. We evaluate seven pathway modules-mitochondrial dynamics, mitophagy, biogenesis, oxidative phosphorylation, nicotinamide adenine dinucleotide (NAD+)/sirtuin (SIRT)-linked regulation, protein import, and the mitochondrial unfolded protein response (UPRmt)-across an evidence map encompassing basic, clinical, and multi-omics studies. Dynamics and mitophagy represent mechanistically central quality-control nodes; their impairment permits dysfunctional organelle accumulation and promotes atrophic cascades. Direct evidence density, however, remains weighted toward oxidative phosphorylation and mitochondrial biogenesis. NAD+/SIRT-linked regulation, protein import fidelity, and UPRmt represent mechanistically upstream but comparatively underinvestigated signals. We propose a diabetes-centered framework where mitochondrial proteostasis failure mediates atrophy and reinforces insulin resistance via a self-amplifying feed-forward loop, supported by pathway responsiveness to coherent interventions. Human multi-omics data highlight network-level dysregulation rather than isolated defects, underscoring module-based biomarker strategies. Translationally, exercise remains the mechanistic cornerstone, while pathway-directed adjuncts-NAD+ precursor repletion, mitophagy modulators, and emerging pharmacotherapeutics-are warranted for patients with identifiable module-specific failure patterns.
    Keywords:  Diabetes mellitus, type 2; Mitophagy; Multiomics; Muscle, skeletal; Proteostasis; Sarcopenia
    DOI:  https://doi.org/10.4093/dmj.2026.0310
  9. Cell Commun Signal. 2026 Sep 09. pii: 481. [Epub ahead of print]24(1):
    Hemifusomes and proteolipid nanodroplets: a critical synthesis of an emerging model for endosomal membrane remodeling.
    Mohammed A Abdel-Rasol, Wael M El-Sayed.
      Vesicular membrane trafficking is central to eukaryotic homeostasis, governing receptor downregulation, lysosomal degradation, and intercellular communication via exosomes. These processes are classically explained by SNARE-mediated fusion and ESCRT-dependent membrane remodeling, which together define current models of vesicle biogenesis and multivesicular body (MVB) formation. Recent high-resolution cryo-electron tomography of intact mammalian cells has identified a structurally distinct membrane-associated assembly termed the hemifusome. Hemifusomes consist of two heterotypic vesicles connected by a persistent hemifusion diaphragm (~ 160 nm in diameter) and feature a ~ 42 nm proteolipid nanodroplet (PND) localized at the diaphragm rim. This architecture expands current views of hemifusion intermediates and raises the possibility of an alternative mode of endosomal membrane organization distinct from canonical ESCRT-mediated processes. However, the molecular composition, biogenesis, and regulatory mechanisms of this system remain undefined. Here, we provide the first integrated synthesis of hemifusome and PND biology, consolidating structural, biophysical, and mechanistic observations within the context of endosomal trafficking. We compare this emerging framework with ESCRT-mediated intraluminal vesicle formation, highlighting both shared features and key mechanistic gaps. We further examine preliminary and largely correlative links to neurodegenerative and lysosomal storage disorders, while emphasizing the absence of direct causal evidence. Given that this field currently rests on a single primary research report, we deliberately separate this evidence-based structural synthesis from more speculative functional, disease-related, and translational extensions, which are presented as explicit future perspectives rather than established conclusions. Finally, we outline unresolved questions, including PND molecular identity, determinants of hemifusion diaphragm organization and stability, and the temporal sequence of hemifusome assembly and remodeling. Together, these findings position hemifusomes as a potentially distinct structural state within the endosomal network, warranting systematic molecular and functional investigation.
    Keywords:  Cryogenic electron tomography; Exosomes; Lipid-protein assemblies; Membrane biophysics; Membrane curvature; Multivesicular bodies
    DOI:  https://doi.org/10.1186/s12964-026-03182-7
  10. Nat Commun. 2026 Aug 10. pii: 9571. [Epub ahead of print]17(1):
    Oxidative stress triggers RNAPII arrest through PARylation and DNA damage.
    Quentin A Thomas, Liyang Wu, Emma Lesage, Henriette K M Iversen, David López Martínez, Smaragda Kompocholi, Haiyue Liu, Nicolás Nieto Moreno, Lea H Gregersen.
      UV or gamma irradiation, as well as certain chemicals, generate DNA damage that disrupts transcription through a variety of well-characterised mechanisms. In contrast, the transcriptional response to oxidative stress remains poorly understood. Here, we describe a rapid and widespread shutdown of transcription following oxidative DNA base damage. By monitoring RNAPII occupancy and elongation dynamics, we demonstrate that oxidative stress temporarily halts RNAPII pause release and arrests the progression of elongation complexes within the gene body. We present evidence that this occurs in a unique and transient manner, characterised by abrupt arrest of elongating RNAPII dead in its tracks, followed by rapid transcriptional recovery as DNA lesions are repaired. We find that the restriction of initiation and early elongation complexes is regulated by PARylation, whereas recovery of RNAPII arrested within the gene body requires DNA repair mediated by the base excision repair (BER) and single-strand break repair (SSBR) pathways.
    DOI:  https://doi.org/10.1038/s41467-026-76443-1
  11. Isr J Chem. 2026 Jul;66(4): e70016
    R17 Drives Heparan Sulfate Clearance via Endolysosomal Trafficking.
    Pranali Bedekar, Alexander Lin, Abigail E Reeves, Meg Critcher, Gil-Suk Yang, Sean Hui, Daved H Fremont, Mia L Huang.
      Heparan sulfate (HS) proteoglycans are information-rich macromolecules that can orchestrate extracellular signaling and cargo uptake across diverse cellular contexts. Ligands that can engage cell surface HS possess significant potential as probes to investigate or manipulate cell-matrix interactions. Here, we show that R17, an HS-binding protein from the rodent herpesvirus Peru, actively remodels the glycocalyx of pancreatic cancer cells. Recombinant R17 bound heparin in vitro and associated with the surface of pancreatic cancer cells to promote the dose-dependent clearance of HS via trafficking to lysosomes. R17 also reduced wound closure without detectable cytotoxicity, indicative of the ability of R17 to suppress cellular migration. Notably, HS depletion persisted upon cation-independent mannose-6-phosphate receptor knockdown, suggesting that clearance is independent of this mechanism. These findings identify R17 as an exogenous HS-binding protein that can drive HS clearance via endolysosomal trafficking and suggest an alternative approach to modulate HS-dependent functions.
    Keywords:  endocytosis; endolysosomal trafficking; glycosaminoglycans; heparan sulfate; heparan sulfate proteoglycans; lysosome; pancreatic cancer
    DOI:  https://doi.org/10.1002/ijch.70016
  12. Front Immunol. 2026 ;17 1921226
    Mitochondrial immunometabolism in sepsis: bridging immune cell dysfunction and organ failure.
    Xingzhan Zhang, Ling Zhao, Wei Fu, Lili Pan, Huanhuan Wu, Jie Peng.
      Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, remains a leading cause of mortality in critical care, and sepsis-associated multiple organ failure continues to defy effective therapy. Increasing evidence positions mitochondria at the interface of cellular bioenergetics and innate immune signaling, making mitochondrial immunometabolism a compelling framework for understanding sepsis pathophysiology. In this mini-review, we synthesize how mitochondrial bioenergetic dysfunction shapes immune cell function across the dynamic course of sepsis, from the glycolytic, oxidative phosphorylation (OXPHOS)-uncoupled state of the hyperinflammatory phase to the bioenergetic failure of the immunoparalytic phase. We examine the contested roles of mitochondrial quality-control mechanisms: mitophagy, dynamics, and biogenesis, in immune cell remodeling, and propose that their net effect follows a time- and cell-type-dependent pattern rather than a fixed protective or deleterious role. We further discuss how mitochondrial damage-associated molecular patterns (mtDAMPs), mitochondrial DNA (mtDNA), reactive oxygen species (mtROS), and remodeled cardiolipin activate the cGAS-STING pathway and the NLRP3 inflammasome and cross-regulate one another to amplify inflammation and drive organ injury. Integrating these themes, we highlight mitochondrial immunometabolic crosstalk between key immune cell subsets (macrophages, neutrophils, and lymphocytes) and the parenchymal cells of vulnerable target organs (heart, kidney, lung, and the gut-liver axis). Finally, we identify knowledge gaps spanning temporal dynamics, cellular heterogeneity, and clinical translation, acknowledge the limitations of the current evidence, and outline emerging therapeutic and monitoring strategies. Collectively, mitochondrial immunometabolism links immune cell dysfunction to organ failure and may guide stage- and endotype-specific interventions in sepsis.
    Keywords:  NLRP3 inflammasome; immune cell dysfunction; immunometabolism; metabolic reprogramming; mitochondria; mitochondrial DNA; multiple organ failure; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2026.1921226
This page is being maintained by Thomas Krichel. It was last updated on 2026‒09‒21 at 12:42.