bims-musmir Biomed News
on microRNAs in muscle
Issue of 2024‒11‒17
seven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. Role of myofiber-specific FoxP1 in pancreatic cancer-induced muscle wasting.
  2. The immune landscape of murine skeletal muscle regeneration and aging.
  3. New perspectives of the role of skeletal muscle derived extracellular vesicles in the pathogenesis of amyotrophic lateral sclerosis: the 'dying back' hypothesis.
  4. Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging.
  5. The circular RNA circNFIX regulates MEF2C expression in muscle satellite cells in spastic cerebral palsy.
  6. Older patients affected by COVID-19: investigating the existence of biological phenotypes.
  7. HuD impairs neuromuscular junctions and induces apoptosis in human iPSC and Drosophila ALS models.
  1. Am J Physiol Cell Physiol. 2024 Nov 15.
    Role of myofiber-specific FoxP1 in pancreatic cancer-induced muscle wasting.
    Martin M Schonk, Jeremy B Ducharme, Daria Neyroud, Rachel L Nosacka, Haley O Tucker, Sarah M Judge, Andrew R Judge.
      Cancer cachexia affects up to 80% of cancer patients and results in reduced quality of life and survival. We previously demonstrated that the transcriptional repressor Forkhead box P1 (FoxP1) is upregulated in skeletal muscle of cachectic mice and people with cancer, and when overexpressed in skeletal muscle is sufficient to induce pathological features characteristic of cachexia. However, the role of myofiber-derived FoxP1 in both normal muscle physiology and cancer-induced muscle wasting remains largely unexplored. To address this gap, we generated a conditional mouse line with myofiber-specific ablation of FoxP1 (FoxP1SkmKO) and found that in cancer-free mice, deletion of FoxP1 in skeletal myofibers resulted in increased myofiber size in both males and females, with a significant increase in muscle mass in males. In response to murine KPC pancreatic tumor burden, we found that myofiber-derived FoxP1 is required for cancer-induced muscle wasting and diaphragm muscle weakness in male mice. In summary, our findings identify myofiber-specific FoxP1 as a negative regulator of skeletal muscle with sex-specific differences in the context of cancer.
    Keywords:  Biological sex; Cancer cachexia; Forkhead box P1; Muscle wasting; Pancreatic cancer
    DOI:  https://doi.org/10.1152/ajpcell.00701.2024
  2. Cell Rep. 2024 Nov 13. pii: S2211-1247(24)01326-3. [Epub ahead of print]43(11): 114975
    The immune landscape of murine skeletal muscle regeneration and aging.
    Neuza S Sousa, Marta Bica, Margarida F Brás, Ana C Sousa, Inês B Antunes, Isabel A Encarnação, Tiago M Costa, Inês B Martins, Nuno L Barbosa-Morais, Pedro Sousa-Victor, Joana Neves.
      Age-related alterations in the immune system are starting to emerge as key contributors to impairments found in aged organs. A decline in regenerative capacity is a hallmark of tissue aging; however, the contribution of immune aging to regenerative failure is just starting to be explored. Here, we apply a strategy combining single-cell RNA sequencing with flow cytometry, histological analysis, and functional assays to perform a complete analysis of the immune environment of the aged regenerating skeletal muscle on a time course following injury with single-cell resolution. Our results reveal an unanticipated complexity and functional heterogeneity in immune populations within the skeletal muscle that have been regarded as homogeneous. Furthermore, we uncover a profound remodeling of both myeloid and lymphoid compartments in aging. These discoveries challenge established notions on immune regulation of skeletal muscle regeneration, providing a set of potential targets to improve skeletal muscle health and regenerative capacity in aging.
    Keywords:  CP: Immunology
    DOI:  https://doi.org/10.1016/j.celrep.2024.114975
  3. J Extracell Biol. 2024 Nov;3(11): e70019
    New perspectives of the role of skeletal muscle derived extracellular vesicles in the pathogenesis of amyotrophic lateral sclerosis: the 'dying back' hypothesis.
    Carolina Sbarigia, Sophie Rome, Luciana Dini, Stefano Tacconi.
      Amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord, and is characterized by muscle weakness, paralysis and ultimately, respiratory failure. The exact causes of ALS are not understood, though it is believed to combine genetic and environmental factors. Until now, it was admitted that motor neurons (MN) in the brain and spinal cord degenerate, leading to muscle weakness and paralysis. However, as ALS symptoms typically begin with muscle weakness or stiffness, a new hypothesis has recently emerged to explain the development of the pathology, that is, the 'dying back hypothesis', suggesting that this degeneration starts at the connections between MN and muscles, resulting in the loss of muscle function. Over time, this damage extends along the length of the MN, ultimately affecting their cell bodies in the spinal cord and brain. While the dying back hypothesis provides a potential framework for understanding the progression of ALS, the exact mechanisms underlying the disease remain complex and not fully understood. In this review, we are positioning the role of extracellular vesicles as new actors in ALS development.
    Keywords:  amyotrophic lateral sclerosis; biomarkers; extracellular vesicles; neuromuscular junctions; skeletal muscle
    DOI:  https://doi.org/10.1002/jex2.70019
  4. J Clin Invest. 2024 Nov 12. pii: e163648. [Epub ahead of print]
    Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging.
    Sara Ancel, Joris Michaud, Eugenia Migliavacca, Charline Jomard, Aurélie Fessard, Pauline Garcia, Sonia Karaz, Sruthi Raja, Guillaume E Jacot, Thibaut Desgeorges, José-Luis Sánchez-García, Loic Tauzin, Yann Ratinaud, Benjamin Brinon, Sylviane Métairon, Lucas Pinero, Denis Barron, Stephanie Blum, Leonidas G Karagounis, Ramin Heshmat, Afshin Ostovar, Farshad Farzadfar, Isabella Scionti, Rémi Mounier, Julien Gondin, Pascal Stuelsatz, Jerome N Feige.
      Skeletal muscle relies on resident muscle stem cells (MuSCs) for growth and repair. Aging and muscle diseases impair MuSC function, leading to stem cell exhaustion and regenerative decline that contribute to the progressive loss of skeletal muscle mass and strength. In the absence of clinically available nutritional solutions specifically targeting MuSCs, we used a human myogenic progenitor (hMP) high-content imaging screen of natural molecules from food to identify nicotinamide (NAM) and pyridoxine (PN) as bioactive nutrients that stimulate MuSCs and have history of safe human use. NAM and PN synergize via CK1-mediated cytoplasmic β-catenin activation and AKT signaling to promote amplification and differentiation of MuSCs. Oral treatment with a combination of NAM/PN accelerates muscle regeneration in vivo by stimulating MuSCs, increases muscle strength during recovery, and overcomes MuSC dysfunction and regenerative failure during aging. Levels of NAM and bioactive PN spontaneously decline during aging in model organisms and inter-independently associate with muscle mass and walking speed in a human cohort of 186 aged people. Collectively, our results establish NAM/PN as a new nutritional intervention that stimulates MuSCs, enhances muscle regeneration, and alleviates age-related muscle decline with a direct opportunity for clinical translation.
    Keywords:  Adult stem cells; Epidemiology; Muscle biology; Skeletal muscle; Stem cells
    DOI:  https://doi.org/10.1172/JCI163648
  5. J Biol Chem. 2024 Nov 12. pii: S0021-9258(24)02489-X. [Epub ahead of print] 107987
    The circular RNA circNFIX regulates MEF2C expression in muscle satellite cells in spastic cerebral palsy.
    Brigette Romero, Parsa Hoque, Karyn G Robinson, Stephanie K Lee, Tanvi Sinha, Amaresh Panda, Michael W Shrader, Vijay Parashar, Robert E Akins, Mona Batish.
      Cerebral palsy (CP) is a pediatric onset disorder with poorly understood molecular causes and progression, making early diagnosis difficult. Circular RNAs (circRNAs) are regulatory RNAs that show promise as biomarkers in various diseases but the role of circRNAs in CP is beginning to be understood. This study identified the role of circNFIX in regulating the expression of MEF2C, an important transcription factor for sarcomere development. We found that circNFIX is downregulated in the muscle cells of individuals with CP, and its localization shifts towards the nucleus as visualized using single molecule resolution imaging. The decreased expression of circNFIX, MEF2C, and MEF2C targets persisted throughout myoblasts to myotubes differentiation, and in the skeletal muscle tissue. Bioinformatic and experimental validation confirmed that circNFIX acts as a sponge for miR373-3p, a microRNA that represses MEF2C translation. In normal muscle, circNFIX de-represses MEF2C translation by sponging miR373-3p, allowing for normal sarcomere generation. In CP, reduced circNFIX expression results in loss of miRNA sponging, leading to lower MEF2C expression and downregulation of sarcomere genes, potentially causing shortened and dysfunctional muscle fibers. Knockdown of circNFIX (KD) reduced myogenic capacity of myoblasts to fuse and form myotubes similar to CP cells evident from the lower fusion index in CP and KD as compared to control myotubes. This the first study reporting reduction of MEF2C in CP and single molecule resolution imaging of circNFIX's subcellular distribution and its role in CP, suggesting circNFIX as a potential therapeutic target and biomarker for early CP diagnosis.
    Keywords:  Biomarker; Cerebral palsy; CircFISH; MEF2C; Satellite cells; circNFIX; circular RNA; miR-373-3p; miRNA sponging; regulatory non-coding RNAs. Spastic Cerebral Palsy
    DOI:  https://doi.org/10.1016/j.jbc.2024.107987
  6. BMC Geriatr. 2024 Nov 07. 24(1): 923
    Older patients affected by COVID-19: investigating the existence of biological phenotypes.
    Alberto Zucchelli, Marta Parigi, Silvia Giliani, Davide Liborio Vetrano, Daniela Lucente, Emanuele Marzetti, Riccardo Calvani, Giuseppe Bellelli, Alessandra Marengoni.
      INTRODUCTION: COVID-19 provides an opportunity to examine biological phenotypes (observable morphological, functional and biological characteristics) in individuals who experience the same acute condition, potentially revealing differences in response to acute external stressors. The aim our study was to investigate biological phenotypes in older patients hospitalized for COVID-19, exploiting a panel of aging biomarkers.METHODS: Data were gathered from the FRACOVID Project, an observational multicenter study, aimed to evaluate the impact of frailty on health-related outcomes in patients 60 + with COVID-19 in Northern Italy. A hierarchical cluster analysis was run using log-transformed and scaled values of TNF-a, IL-1 beta, IL-6, PAI-1, GDF-15, NT-proBNP, and Cystatin C evaluated at admission.
    RESULTS: Eighty-one participants (mean age 75.3 years; 60.5% male) were evaluated. Frailty was identified in 42% of the sample and 27.2% were unable to ambulate outdoors. The mean hospital stay was 24.7 days, with an in-hospital mortality rate of 18.5%. Three biological phenotypes were found: (1) 'inflammatory', with high inflammatory biomarkers; (2) 'organ dysfunction', characterized by elevated cystatin C and NT-proBNP, and lower inflammatory markers; and (3) 'unspecific', with lower NT-proBNP and GDF-15 levels, and intermediate concentrations of other biomarkers. The 'organ dysfunction' phenotype showed the highest mean age and prevalence of frailty, disability, and chronic diseases. The 'inflammatory' phenotype showed the highest burden of respiratory and systemic signs and symptoms of infection.
    CONCLUSION: Biological phenotypes might be used to identify different clinical and functional phenotypes in individuals affected by COVID-19.
    Keywords:  Biomarkers; COVID-19; Elderly; Frailty
    DOI:  https://doi.org/10.1186/s12877-024-05473-5
  7. Nat Commun. 2024 Nov 07. 15(1): 9618
    HuD impairs neuromuscular junctions and induces apoptosis in human iPSC and Drosophila ALS models.
    Beatrice Silvestri, Michela Mochi, Darilang Mawrie, Valeria de Turris, Alessio Colantoni, Beatrice Borhy, Margherita Medici, Eric Nathaniel Anderson, Maria Giovanna Garone, Christopher Patrick Zammerilla, Marco Simula, Monica Ballarino, Udai Bhan Pandey, Alessandro Rosa.
      Defects at the neuromuscular junction (NMJ) are among the earliest hallmarks of amyotrophic lateral sclerosis (ALS). According to the "dying-back" hypothesis, NMJ disruption not only precedes but also triggers the subsequent degeneration of motoneurons in both sporadic (sALS) and familial (fALS) ALS. Using human induced pluripotent stem cells (iPSCs), we show that the RNA-binding protein HuD (ELAVL4) contributes to NMJ defects and apoptosis in FUS-ALS. HuD overexpression mimics the severe FUSP525L mutation, while its knockdown rescues the FUSP525L phenotypes. In Drosophila, neuronal overexpression of the HuD ortholog, elav, induces motor dysfunction, and its knockdown improves motor function in a FUS-ALS model. Finally, we report increased HuD levels upon oxidative stress in human motoneurons and in sALS patients with an oxidative stress signature. Based on these findings, we propose that HuD plays a role downstream of FUS mutations in fALS and in sALS related to oxidative stress.
    DOI:  https://doi.org/10.1038/s41467-024-54004-8
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒17 at 9:13.