bims-musmir 2025-02-16 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–02–16
eight papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Microbiota protect against frailty, loss of skeletal muscle, and maintain inflammatory tone during aging in mice.
Polyamine metabolism dysregulation contributes to muscle fiber vulnerability in ALS.
Tumor-derived miR-203a-3p potentiates muscle wasting by inducing muscle ferroptosis in pancreatic cancer.
Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men.
Secretory mitophagy: an extracellular vesicle-mediated adaptive mechanism for cancer cell survival under oxidative stress.
5-aza-2-deoxycytidine improves skeletal muscle function in a mouse model for recessive RYR1-related congenital myopathy.
Niacin ameliorates Charcot-Marie-Tooth 4B1 neuropathy without interfering with nerve regeneration.
fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans.

Am J Physiol Cell Physiol. 2025 Feb 10.

Microbiota protect against frailty, loss of skeletal muscle, and maintain inflammatory tone during aging in mice.

Meghan O Conn, Erica N DeJong, Daniel M Marko, Russta Fayyazi, Dana Kukje Zada, Kevin P Foley, Nicole G Barra, Dawn M E Bowdish, Jonathan D Schertzer.

  Chronic low-level inflammation or "inflammaging" is hypothesized to contribute to sarcopenia and frailty. Resident microbiota are thought to promote inflammaging, frailty, and loss of skeletal muscle mass. We tested immunity and frailty in male C57BL6/N germ-free (GF), specific-pathogen-free (SPF), and mice that were born germ-free and colonized (COL) with an SPF microbiota. Male and female GF mice had lower systemic cellular inflammation indicated by lower blood Ly6Chigh monocytes across their lifespan. Male GF mice had lower body mass, but relative to body mass, GF mice had smaller hindlimb muscles and smaller muscle fibers compared to SPF mice across the lifespan. Male and female GF mice had increased frailty at 18 months or older. Colonization of female GF mice increased blood Ly6Chigh monocytes, but did not affect frailty at 18 months or older. Colonization of male GF mice increased blood Ly6Chigh monocytes, skeletal muscle size, myofiber fiber size, and decreased frailty at 18 months or older. Transcriptomic analysis of the tibialis anterior muscle revealed a microbiota-muscle axis with over 550 differentially expressed genes in COL male mice at 18 months or older. Colonized male mice had transcripts indicative of lower tumor necrosis factor-alpha (TNF) signaling via nuclear factor κB (NF-κB). Our findings show that microbiota can increase systemic cellular immunity, while decreasing muscle inflammation, thereby protecting against muscle loss and frailty. We also found sex differences in the role of microbiota regulating frailty. We propose that microbiota components protect against lower muscle mass and frailty across the lifespan in mice.

Keywords:  Aging; Gut Microbiota; Muscle; Sarcopenia

DOI:  https://doi.org/10.1152/ajpcell.00869.2024
Cell Rep. 2025 Jan 28. pii: S2211-1247(24)01474-8. [Epub ahead of print]44(1): 115123

Polyamine metabolism dysregulation contributes to muscle fiber vulnerability in ALS.

Veronica Ruggieri, Silvia Scaricamazza, Andrea Bracaglia, Chiara D'Ercole, Cristina Parisi, Paolo D'Angelo, Daisy Proietti, Chiara Cappelletti, Alberto Macone, Biliana Lozanoska-Ochser, Marina Bouchè, Lucia Latella, Cristiana Valle, Alberto Ferri, Lorenzo Giordani, Luca Madaro.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing progressive paralysis due to motor neuron degeneration with no curative therapy despite extensive biomedical research. One of the primary targets of ALS is skeletal muscle, which undergoes profound functional changes as the disease progresses. To better understand how altered innervation interferes with muscle homeostasis during disease progression, we generated a spatial transcriptomics dataset of skeletal muscle in the SOD1G93A mouse model of ALS. Using this strategy, we identified polyamine metabolism as one of the main altered pathways in affected muscle fibers. By establishing a correlation between the vulnerability of muscle fibers and the dysregulation of this metabolic pathway, we show that disrupting polyamine homeostasis causes impairments similar to those seen in ALS muscle. Finally, we show that restoration of polyamine homeostasis rescues the muscle phenotype in SOD1G93A mice, opening new perspectives for the treatment of ALS.

Keywords:  CP: Metabolism; CP: Neuroscience; amyotrophic lateral sclerosis; muscular atrophy; neuromuscular junction; polyamines; skeletal muscle; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2024.115123
Cancer Lett. 2025 Feb 06. pii: S0304-3835(25)00087-4. [Epub ahead of print]614 217523

Tumor-derived miR-203a-3p potentiates muscle wasting by inducing muscle ferroptosis in pancreatic cancer.

Yumeng Hu, Yifu Hu, Shaobo Zhang, Yuanyuan Guo, Fangxia Wang, Yongxing Du, Lijuan Wang, Pengxue Li, Yan Xu, Hui Zhang, Zhikai Yang, Zhihua Liu, Jingyong Xu, Mingyang Liu.

  Pancreatic cancer (PC) cachexia, characterized by profound muscle wasting and systemic inflammation, remains a formidable clinical challenge due to its multifactorial nature and complex molecular underpinnings. This study delves into the intricate interplay between microRNA (miRNA) dysregulation and ferroptosis, a form of iron-dependent cell death, in PC cachexia. Specifically, we identified tumor-derived miR-203a-3p as a pivotal miRNA that promotes muscle atrophy by upregulating muscle ferroptosis. Our findings revealed that miR-203a-3p targets zinc finger E-box binding homeobox 1 (ZEB1), subsequently enhancing the expression of the iron transporter solute carrier family 11 member 2 (SLC11A2), thereby facilitating ferroptosis-associated skeletal muscle cell death. Through in vivo experiments using a PC cachexic mouse model, we demonstrated that inhibiting ferroptosis effectively attenuated muscle wasting, highlighting its critical role in the pathogenesis of PC cachexia. These results provide a molecular framework elucidating how miRNA regulation and ferroptosis converge to drive muscle atrophy, offering novel therapeutic avenues for mitigating cachexia in PC patients. By targeting these pathways, we aim to improve muscle preservation and overall survival in this devastating disease.

Keywords:  Cachexia; Ferroptosis; Pancreatic cancer; SLC11A2; miR-203a-3p

DOI:  https://doi.org/10.1016/j.canlet.2025.217523
Cell Rep Med. 2025 Feb 06. pii: S2666-3791(25)00041-2. [Epub ahead of print] 101968

Impact of physical activity on physical function, mitochondrial energetics, ROS production, and Ca2+ handling across the adult lifespan in men.

Marina Cefis, Vincent Marcangeli, Rami Hammad, Jordan Granet, Jean-Philippe Leduc-Gaudet, Pierrette Gaudreau, Caroline Trumpff, Qiuhan Huang, Martin Picard, Mylène Aubertin-Leheudre, Marc Bélanger, Richard Robitaille, José A Morais, Gilles Gouspillou.

  Aging-related muscle atrophy and weakness contribute to loss of mobility, falls, and disability. Mitochondrial dysfunction is widely considered a key contributing mechanism to muscle aging. However, mounting evidence positions physical activity as a confounding factor, making unclear whether muscle mitochondria accumulate bona fide defects with aging. To disentangle aging from physical activity-related mitochondrial adaptations, we functionally profiled skeletal muscle mitochondria in 51 inactive and 88 active men aged 20-93. Physical activity status confers partial protection against age-related decline in physical performance. Mitochondrial respiration remains unaltered in active participants, indicating that aging per se does not alter mitochondrial respiratory capacity. Mitochondrial reactive oxygen species (ROS) production is unaffected by aging and higher in active participants. In contrast, mitochondrial calcium retention capacity decreases with aging regardless of physical activity and correlates with muscle mass, performance, and the stress-responsive metabokine/mitokine growth differentiation factor 15 (GDF15). Targeting mitochondrial calcium handling may hold promise for treating aging-related muscle impairments.

Keywords:  calcium retention capacity; functional capacities; intermuscular fat accumulation; mitochondria; mitochondrial permeability transition pore; muscle atrophy and weakness; physical performance; reactive oxygen species; sarcopenia; skeletal muscle aging

DOI:  https://doi.org/10.1016/j.xcrm.2025.101968
Front Cell Dev Biol. 2024 ;12 1490902

Secretory mitophagy: an extracellular vesicle-mediated adaptive mechanism for cancer cell survival under oxidative stress.

Purva V Gade, Angela Victoria Rojas Rivera, Layla Hasanzadah, Sofie Strompf, Thomas Raymond Philipson, Matthew Gadziala, Atharva Tyagi, Arnav Bandam, Rithvik Gabbireddy, Fatah Kashanchi, Amanda Haymond, Lance A Liotta, Marissa A Howard.

  Mitophagy is a critically important survival mechanism in which toxic, aged, or defective mitochondria are segregated into mitophagosomes, which shuttle the damaged mitochondrial segments to the lysosome and proteasome for destruction. Cancer cells rely on mitophagy under conditions of high oxidative stress or increased energy demand. Oxidative stress can generate a large volume of damaged mitochondria, overwhelming lysosomal removal. Accumulated damaged mitochondria are toxic and their proper removal is crucial for maintaining mitochondrial health. We propose a new cancer cell mechanism for survival that is activated when the demand for segregating and eliminating damaged mitochondria exceeds the capacity of the lysosome or proteasome. Specifically, we show that tumor cells subjected to oxidative stress by carbonyl cyanide-3-chlorophenylhdrazone (CCCP) eliminate damaged mitochondria segments by bypassing the lysosome to export them outside the cell via extracellular vesicles (EVs), a process termed "secretory mitophagy". PINK1, the initiator of mitophagy, remains associated with the damaged mitochondria that exported in EVs. Using several types of cancer cells, we show that tumor cells treated with CCCP can be induced to switch over to secretory mitophagy by treatment with Bafilomycin A1, which blocks the fusion of mitophagosomes with lysosomes. Under these conditions, an increased number of PINK1 + EVs are exported. This is associated with greater cell survival by a given CCCP dose, enhanced mitochondrial ATP production, and reduced mitochondrial oxidative damage (membrane depolarization). Our data supports the hypothesis that secretory mitophagy is a previously unexplored process by which cancer cells adapt to survive therapeutic or hypoxic stress. Ultimately, our findings may inform new prevention strategies targeting pre-malignant lesions and therapeutic approaches designed to sensitize tumor cells to oxidative stress-inducing therapies.

Keywords:  PINK1; cancer progression; cell survival; extracellular vesicles; mitophagy; oxidative stress

DOI:  https://doi.org/10.3389/fcell.2024.1490902
Hum Mol Genet. 2025 Feb 13. pii: ddaf021. [Epub ahead of print]

5-aza-2-deoxycytidine improves skeletal muscle function in a mouse model for recessive RYR1-related congenital myopathy.

Alexis Ruiz, Faiza Noreen, Hervé Meier, Katarzyna Buczak, Francesco Zorzato, Susan Treves.

  RYR1-related congenital myopathies are rare disorders that severely impair muscle function and the quality of life of patients and their families. To date no pharmacological therapies are available to treat the severe muscle weakness of affected patients. The most severe forms of RYR1-related congenital myopathies are caused by compound heterozygous mutations (nonsense/frameshift in one allele and a missense mutation in the other), leading to reduced RyR1 protein levels and altered biochemical composition of muscles. In this pre-clinical study, we treated a mouse model carrying the RyR1 p.Q1970fsX16 + p.A4329D compound heterozygous pathogenic variants (dHT mice) for 15 weeks with 0.05 mg/kg 5-aza-2'-deoxycytidine, an FDA-approved drug targeting DNA methyltransferases. We evaluated muscle strength, calcium homeostasis and muscle proteome and report that drug treatment improves all investigated parameters in dHT mice. Importantly, the beneficial effects were particularly significant in fast twitch muscles which are the first muscles to be impaired in patients. In conclusion, this study provides proof of concept for the pharmacological treatment of patients with recessive RYR1-related congenital myopathies with the FDA approved 5-aza-2'-deoxycytidine, supporting its use in a phase 1/2 clinical trial.

Keywords:  5-Aza; Congenital myopathies; Epigenetic changes; Improved muscle function; RYR1

DOI:  https://doi.org/10.1093/hmg/ddaf021
Brain Commun. 2025 ;7(1): fcaf039

Niacin ameliorates Charcot-Marie-Tooth 4B1 neuropathy without interfering with nerve regeneration.

Silvia Cipriani, Emanuela Porrello, Matteo Cerea, Andrea Gazzaniga, Roberta Di Guardo, Amanda Heslegrave, Serena Valenzano, Ubaldo Del Carro, Phu Duong, John Svaren, Stefano Carlo Previtali, Alessandra Bolino.

  Charcot-Marie-Tooth (CMT) neuropathies represent a broad and very heterogeneous group of disorders for which no therapies are yet available. Due to the huge genetic heterogeneity, therapeutical approaches that can benefit several forms independently of the unique pathogenetic mechanism have been sought. Niacin, nicotinic acid, is a vitamin used for many decades as anti-dyslipidaemic and anti-cholesterol drug product under the commercial name of Niaspan®, the extended-release formulation of niacin. Of note, niacin can have other effects depending on the dose, formulation and physiology and it has been used to reduce inflammation, to promote angiogenesis and to protect neurons, muscle and axons by boosting nicotinamide adenine dinucleotide (NAD+) levels. Niacin also activates TNF-alpha convertase enzyme (TACE) secretase, which negatively regulates Neuregulin type I-mediated signalling in the peripheral nervous system and myelination. We previously postulated that niacin-mediated TACE activation can be effective in reducing aberrant excessive myelin associated with different CMT forms. Here, we explored efficacy of this strategy by performing a long-term preclinical trial and we provided evidence that a novel niacin-based long-lasting formulation ameliorates neurophysiology and reduces fibre degeneration in a model of Charcot-Marie-Tooth type 4B1 (CMT4B1) neuropathy, characterized by aberrant myelin. We also sought to determine whether this strategy might interfere with nerve regeneration, which is dependent on Neuregulin type I signalling. Surprisingly, we found that the Mtmr2 knockout mice, a model of CMT4B1, have a defect in nerve regeneration and that niacin-based treatment is not detrimental to nerve regeneration.

Keywords:  Charcot-Marie-Tooth; myelin; nerve regeneration; neuropathy; nicotinic acid

DOI:  https://doi.org/10.1093/braincomms/fcaf039
Elife. 2025 Feb 14. pii: RP99971. [Epub ahead of print]13

fmo-4 promotes longevity and stress resistance via ER to mitochondria calcium regulation in C. elegans.

Angela M Tuckowski, Safa Beydoun, Elizabeth S Kitto, Ajay Bhat, Marshall B Howington, Aditya Sridhar, Mira Bhandari, Kelly Chambers, Scott F Leiser.

  Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that C. elegans fmo-2 promotes longevity, stress resistance, and healthspan by rewiring endogenous metabolism. However, there are five C. elegans FMOs and five mammalian FMOs, and it is not known whether promoting longevity and health benefits is a conserved role of this gene family. Here, we report that expression of C. elegans fmo-4 promotes lifespan extension and paraquat stress resistance downstream of both dietary restriction and inhibition of mTOR. We find that overexpression of fmo-4 in just the hypodermis is sufficient for these benefits, and that this expression significantly modifies the transcriptome. By analyzing changes in gene expression, we find that genes related to calcium signaling are significantly altered downstream of fmo-4 expression. Highlighting the importance of calcium homeostasis in this pathway, fmo-4 overexpressing animals are sensitive to thapsigargin, an ER stressor that inhibits calcium flux from the cytosol to the ER lumen. This calcium/fmo-4 interaction is solidified by data showing that modulating intracellular calcium with either small molecules or genetics can change expression of fmo-4 and/or interact with fmo-4 to affect lifespan and stress resistance. Further analysis supports a pathway where fmo-4 modulates calcium homeostasis downstream of activating transcription factor-6 (atf-6), whose knockdown induces and requires fmo-4 expression. Together, our data identify fmo-4 as a longevity-promoting gene whose actions interact with known longevity pathways and calcium homeostasis.

Keywords:  C. elegans; ER; aging; calcium; flavin-containing monooxygenase; genetics; genomics; mitochondria; stress resistance

DOI:  https://doi.org/10.7554/eLife.99971