bims-musmir Biomed News
on microRNAs in muscle
Issue of 2025–02–02
seven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. Tissue-resident skeletal muscle macrophages promote recovery from viral pneumonia-induced sarcopenia in normal aging.
  2. Fibroblast growth factor-inducible 14 regulates satellite cell self-renewal and expansion during skeletal muscle repair.
  3. Sporadic ALS iPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways.
  4. NAD World 3.0: the importance of the NMN transporter and eNAMPT in mammalian aging and longevity control.
  5. An Addendum to the Chemiosmotic Theory of Mitochondrial Activity: The Role of RNA as a Proton Sink.
  6. PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response.
  7. Responses of skeletal muscle to mechanical stimuli in female rats following and during muscle disuse atrophy.
  1. bioRxiv. 2025 Jan 14. pii: 2025.01.09.631996. [Epub ahead of print]
    Tissue-resident skeletal muscle macrophages promote recovery from viral pneumonia-induced sarcopenia in normal aging.
    Constance E Runyan, Lucy Luo, Lynn C Welch, Ziyan Lu, Fei Chen, Maxwell J Schleck, Radmila A Nafikova, Rogan A Grant, Raul Piseaux Aillon, Karolina J Senkow, Elsie G Bunyan, William T Plodzeen, Hiam Abdala-Valencia, Craig Weiss, Laura A Dada, Edward B Thorp, Jacob I Sznajder, Navdeep S Chandel, Alexander V Misharin, G R Scott Budinger.
      Sarcopenia, which diminishes lifespan and healthspan in the elderly, is commonly exacerbated by viral pneumonia, including influenza and COVID-19. In a study of influenza A pneumonia in mice, young mice fully recovered from sarcopenia, while older mice did not. We identified a population of tissue-resident skeletal muscle macrophages that form a spatial niche with satellite cells and myofibers in young mice but are lost with age. Mice with a gain-of-function mutation in the Mertk receptor maintained this macrophage-myofiber interaction during aging and fully recovered from influenza-induced sarcopenia. In contrast, deletion of Mertk in macrophages or loss of Cx3cr1 disrupted this niche, preventing muscle regeneration. Heterochronic parabiosis did not restore the niche in old mice. These findings suggest that age-related loss of Mertk in muscle tissue-resident macrophages disrupts the cellular signaling necessary for muscle regeneration after viral pneumonia, offering a potential target to mitigate sarcopenia in aging.
    DOI:  https://doi.org/10.1101/2025.01.09.631996
  2. JCI Insight. 2025 Jan 28. pii: e187825. [Epub ahead of print]
    Fibroblast growth factor-inducible 14 regulates satellite cell self-renewal and expansion during skeletal muscle repair.
    Meiricris Tomaz da Silva, Aniket S Joshi, Ashok Kumar.
      Skeletal muscle regeneration in adults is predominantly driven by satellite cells. Loss of satellite cell pool and function leads to skeletal muscle wasting in many conditions and disease states. Here, we demonstrate that the levels of fibroblast growth factor-inducible 14 (Fn14) were increased in satellite cells after muscle injury. Conditional ablation of Fn14 in Pax7-expressing satellite cells drastically reduced their expansion and skeletal muscle regeneration following injury. Fn14 was required for satellite cell self-renewal and proliferation as well as to prevent precocious differentiation. Targeted deletion of Fn14 inhibited Notch signaling but led to the spurious activation of STAT3 signaling in regenerating skeletal muscle and in cultured muscle progenitor cells. Silencing of STAT3 improved proliferation and inhibited premature differentiation of Fn14-deficient satellite cells. Furthermore, conditional ablation of Fn14 in satellite cells exacerbated myopathy in the mdx mouse model of Duchenne muscular dystrophy (DMD) whereas its overexpression improved the engraftment of exogenous muscle progenitor cells into the dystrophic muscle of mdx mice. Altogether, our study highlights the crucial role of Fn14 in the regulation of satellite cell fate and function and suggests that Fn14 can be a potential molecular target to improve muscle regeneration in muscular disorders.
    Keywords:  Cell biology; Muscle biology; Neuromuscular disease; Signal transduction; Skeletal muscle; Stem cells
    DOI:  https://doi.org/10.1172/jci.insight.187825
  3. Neurobiol Dis. 2025 Jan 28. pii: S0969-9961(25)00031-2. [Epub ahead of print] 106815
    Sporadic ALS iPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways.
    Lisha Ye, Katarina Stoklund Dittlau, Adria Sicart, Rekin''s Janky, Philip Van Damme, Ludo Van Den Bosch.
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and progressive loss of motor neurons, leading to gradual paralysis and death within 2 to 5 years after diagnosis. The exact underlying pathogenic mechanism(s) remain elusive. This is particularly the case for sporadic ALS (sALS), representing 90 % of cases, as modelling a sporadic disease is extremely difficult. We used human induced pluripotent stem cell (hiPSC)-derived motor neurons from sALS patients to investigate early disease mechanisms. The earliest phenotype that we observed were profound axonal defects including impaired axonal transport, defective axonal outgrowth and a reduced formation of neuromuscular junctions. Transcriptomic profiling revealed significant dysregulation in axon guidance pathways, with upregulation of specific axonal regeneration-inhibiting genes, such as EphA4 and DCC in sALS motor neurons. Our findings suggest that dysregulation of axon guidance pathways contributes to axonal defects and that this could play a crucial role in the pathogenesis of sALS.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Axon guidance; Axonal outgrowth; Axonal transport; Human induced pluripotent stem cells (hiPSCs); Neuromuscular junctions; Sporadic ALS
    DOI:  https://doi.org/10.1016/j.nbd.2025.106815
  4. NPJ Aging. 2025 Jan 27. 11(1): 4
    NAD World 3.0: the importance of the NMN transporter and eNAMPT in mammalian aging and longevity control.
    Shin-Ichiro Imai.
      Over the past five years, systemic NAD+ (nicotinamide adenine dinucleotide) decline has been accepted to be a key driving force of aging in the field of aging research. The original version of the NAD World concept was proposed in 2009, providing an integrated view of the NAD+-centric, systemic regulatory network for mammalian aging and longevity control. The reformulated version of the concept, the NAD World 2.0, was then proposed in 2016, emphasizing the importance of the inter-tissue communications between the hypothalamus and peripheral tissues including adipose tissue and skeletal muscle. There has been significant progress in our understanding of the importance of nicotinamide mononucleotide (NMN), a key NAD+ intermediate, and nicotinamide phosphoribosyltransferase (NAMPT), particularly extracellular NAMPT (eNAMPT). With these exciting developments, the further reformulated version of the concept, the NAD World 3.0, is now proposed, featuring multi-layered feedback loops mediated by NMN and eNAMPT for mammalian aging and longevity control.
    DOI:  https://doi.org/10.1038/s41514-025-00192-6
  5. Biomolecules. 2025 Jan 08. pii: 87. [Epub ahead of print]15(1):
    An Addendum to the Chemiosmotic Theory of Mitochondrial Activity: The Role of RNA as a Proton Sink.
    Ramin M Farahani.
      Mitochondrial ATP synthesis is driven by harnessing the electrochemical gradient of protons (proton motive force) across the mitochondrial inner membrane via the process of chemiosmosis. While there is consensus that the proton gradient is generated by components of the electron transport chain, the mechanism by which protons are supplied to ATP synthase remains controversial. As opposed to a global coupling model whereby protons diffuse into the intermembrane space, a localised coupling model predicts that protons remain closely associated with the lipid membrane prior to interaction with ATP synthase. Herein, a revised version of the chemiosmotic theory is proposed by introducing an RNA-based proton sink which aligns the release of sequestered protons to availability of ADP and Pi thereby maximising the efficiency of oxidative phosphorylation.
    Keywords:  RNA; chemiosmosis; proton motive force; proton sink
    DOI:  https://doi.org/10.3390/biom15010087
  6. Elife. 2025 Jan 29. pii: RP102852. [Epub ahead of print]13
    PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response.
    Ling Cheng, Ian Meliala, Yidi Kong, Jingyuan Chen, Christopher G Proud, Mikael Björklund.
      Mitochondrial dysfunction is involved in numerous diseases and the aging process. The integrated stress response (ISR) serves as a critical adaptation mechanism to a variety of stresses, including those originating from mitochondria. By utilizing mass spectrometry-based cellular thermal shift assay (MS-CETSA), we uncovered that phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitory protein (RKIP), is thermally stabilized by stresses which induce mitochondrial ISR. Depletion of PEBP1 impaired mitochondrial ISR activation by reducing eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and subsequent ISR gene expression, which was independent of PEBP1's role in inhibiting the RAF/MEK/ERK pathway. Consistently, overexpression of PEBP1 potentiated ISR activation by heme-regulated inhibitor (HRI) kinase, the principal eIF2α kinase in the mitochondrial ISR pathway. Real-time interaction analysis using luminescence complementation in live cells revealed an interaction between PEBP1 and eIF2α, which was disrupted by eIF2α S51 phosphorylation. These findings suggest a role for PEBP1 in amplifying mitochondrial stress signals, thereby facilitating an effective cellular response to mitochondrial dysfunction. Therefore, PEBP1 may be a potential therapeutic target for diseases associated with mitochondrial dysfunction.
    Keywords:  PEBP1; cell biology; human; integrated stress response; mitochondrial dysfunction
    DOI:  https://doi.org/10.7554/eLife.102852
  7. J Appl Physiol (1985). 2025 Jan 30.
    Responses of skeletal muscle to mechanical stimuli in female rats following and during muscle disuse atrophy.
    A B Sklivas, Z R Hettinger, S Rose, A Mantuano, A L Confides, S Rigsby, F F Peelor, B F Miller, T A Butterfield, E E Dupont-Versteegden.
      The purpose of this study was to investigate the ability of mechanotherapy to enhance recovery or prevent loss of muscle size with atrophy, in female rats. Female F344/BN rats were assigned to weight bearing (WB), hindlimb suspended (HS) for 14 days with reambulation for 7 days without (RA) or with (RAM) mechanotherapy (study 1), or to WB, HS for 7 days, with (HSM) or without mechanotherapy (study 2) to gastrocnemius. Muscle fiber cross sectional area (CSA) and type, collagen, satellite cell number, and protein synthesis (Ksyn) and degradation (Kdeg) were assessed. Study 1: muscle weight, but not CSA, was higher in RAM compared to HS, but CSA was higher in RA compared to HS. Myofibrillar Ksyn was higher in RA and RAM compared to WB and HS, but not different between RA and RAM. Myofibrillar Kdeg was lower with mechanotherapy compared to HS. Study 2: muscle weight, CSA, and myofibrillar Ksyn and Kdeg were not different with mechanotherapy. Collagen content was lower with mechanotherapy, but collagen Ksyn was not. Mechanotherapy was not associated with changes in fiber type, satellite cell or myonuclear number in either study. Compared to male, female rats had less muscle loss with HS, which was associated with less loss of myofibrillar Ksyn. Recovery from atrophy was associated with higher Ksyn in female and lower Kdeg in male rats. Conclusion: Female rat muscles do not exhibit a growth response to mechanotherapy with disuse or reambulation. Furthermore, male and female rats show distinct responses to different mechanical stimuli.
    Keywords:  Disuse atrophy; massage; mechanosensing; muscle growth; sex differences
    DOI:  https://doi.org/10.1152/japplphysiol.00802.2024
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