bims-musmir 2025-05-04 papers

Exerc Sport Sci Rev. 2025 May 01.

Novel Insights to Mitochondrial Impact in Aging Skeletal Muscle.

Maya Semel, Cole Lukasiewicz, Russell T Hepple.

ABSTRACT: Our Perspective for Progress highlights sex differences in skeletal muscle mitochondrial function that evolve with aging, with an influence of denervation emerging in advanced age. Gaps include knowledge about mitochondrial alterations in microdomains of muscle fibers, plasticity of the mitochondrial reticulum to acute muscle contractions, and advanced age of both sexes.

Keywords: Mitochondria; aging; denervation; heterogeneity; skeletal muscle

DOI: https://doi.org/10.1249/JES.0000000000000364

Am J Physiol Endocrinol Metab. 2025 Apr 29.

Human Skeletal Muscle Disuse Atrophy has Profound and Negative Effects on the Muscle Metabolome and Lipidome.

Sean P Kilroe, Zachary Von Ruff, Emily J Arentson-Lantz, Trevor B Romsdahl, Jennifer J Linares, Hanna Kalenta, Erik D Marchant, Elena Volpi, Douglas Paddon-Jones, William K Russell, Blake B Rasmussen.

We investigated how short-term muscle disuse altered the skeletal muscle metabolome, lipidome and transcriptome in middle-aged adults. We report that the energy metabolism pathways: Nicotinate and nicotinamide metabolism, glycolysis and TCA cycle, were reduced after 7 days of muscle disuse. These changes in the metabolome were reflected by changes in the transcriptome where multiple genes involved in the glycolysis and TCA pathways were reduced after short term disuse. Phenylalanine, tyrosine and tryptophan metabolism pathways showed the same response and were reduced after short-term disuse. The skeletal muscle lipidome showed a decrease in phosphatidylinositols but an increase in phosphatidylglycerols and diacylglycerols after short term muscle disuse. We conclude that short-term muscle disuse in humans has profound and negative effects on the muscle metabolome and lipidome. These include significant downregulation of muscle glycolytic, amino acid, and TCA cycle intermediates. In contrast skeletal muscle lipids had a divergent response to disuse (e.g., increased phosphatidylglycerols and diacylglycerols, but reduced phosphatidylinositols).

Keywords: Skeletal muscle; atrophy; disuse; lipidomics; metabolomics; transcriptomics

DOI: https://doi.org/10.1152/ajpendo.00012.2025

Cell Mol Life Sci. 2025 Apr 28. 82(1): 178

Muscle mTOR controls iron homeostasis and ferritinophagy via NRF2, HIFs and AKT/PKB signaling pathways.

Agnès Conjard-Duplany, Alexis Osseni, Aline Lamboux, Sandrine Mouradian, Flavien Picard, Vincent Moncollin, Céline Angleraux, Tiphaine Dorel-Dubois, Hélène Puccio, Pascal Leblanc, Bruno Galy, Vincent Balter, Laurent Schaeffer, Yann-Gaël Gangloff.

Balanced mTOR activity and iron levels are crucial for muscle integrity, with evidence suggesting mTOR regulates cellular iron homeostasis. In this study, we investigated iron metabolism in muscle-specific mTOR knockout mice (mTORmKO) and its relation to their myopathy. The mTORmKO mice exhibited distinct iron content patterns across muscle types and ages. Slow-twitch soleus muscles initially showed reduced iron levels in young mice, which increased with the dystrophy progression but remained within control ranges. In contrast, the less affected fast-twitch muscles maintained near-normal iron levels from a young age. Interestingly, both mTORmKO muscle types exhibited iron metabolism markers indicative of iron excess, including decreased transferrin receptor 1 (TFR1) and increased levels of ferritin (FTL) and ferroportin (FPN) proteins. Paradoxically, these changes were accompanied by downregulated Ftl and Fpn mRNA levels, indicating post-transcriptional regulation. This discordant regulation resulted from disruption of key iron metabolism pathways, including NRF2/NFE2L2, HIFs, and AKT/PKB signaling. Mechanistically, mTOR deficiency impaired transcriptional regulation of iron-related genes mediated by NRF2 and HIFs. Furthermore, it triggered ferritin accumulation through two NRF2 mechanisms: (1) derepression of ferritin translation via suppression of the FBXL5-IRP axis, and (2) autophagosomal sequestration driven by NCOA4-dependent ferritin targeting to autophagosomes, coupled with age-related impairments of autophagy linked to chronic AKT/PKB activation. Three-week spermidine supplementation in older mTORmKO mice was associated with normalized AKT/PKB-FOXO signaling, increased endolysosomal FTL and reduced total FTL levels in the dystrophic soleus muscle. These findings underscore mTOR's crucial role in skeletal muscle iron metabolism and suggest spermidine as a potential strategy to address impaired ferritinophagy due to autophagy blockade in dystrophic muscle.

Keywords: Autophagy; Dystrophy; Glycogen; Iron-sulfur cluster; Myoglobin; Oxidative stress

DOI: https://doi.org/10.1007/s00018-025-05695-9

Cell Metab. 2025 Apr 24. pii: S1550-4131(25)00212-8. [Epub ahead of print]

NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.

Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD+ abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.

Keywords: NAD metabolism; NAD(+) biosynthesis; NAMPT; aging; epigenetic clock; exercise; mitochondrial supercomplexes; nicotinamide; reactive oxygen species; skeletal muscle

DOI: https://doi.org/10.1016/j.cmet.2025.04.002

Bull Exp Biol Med. 2025 Mar;178(5): 593-596

Subtypes of P2 Receptors in Rat Neuromuscular Junction.

A E Khairullin, A N Khabibrakhmanov, D V Efimova, D V Samigullin, S N Grishin, M A Mukhamedyarov, A U Ziganshin.

At the neuromuscular junction, ATP and its metabolite adenosine regulate the release of acetylcholine by activating purinergic receptors (P2), thereby regulating the function of skeletal muscles under normal and pathological conditions. The presence of P2 receptors in the neuromuscular junction was assessed immunohistochemically on sections of m. soleus, m. extensor digitorum longus, and diaphragm muscle. Of the ionotropic P2X receptors, P2X1 and P2X2 subtypes showed high expression in the studied samples. Among the P2Y receptor family, only the P2Y13 subtype was expressed in the sections. This study provides new insight into the subtypes of purinergic receptors involved in controlling the cholinergic transmission in the mammalian neuromuscular system.

Keywords: P2 receptors; ; neuromuscular synapse; neurotransmission; skeletal muscles

DOI: https://doi.org/10.1007/s10517-025-06380-4

Brain. 2025 Apr 29. pii: awaf153. [Epub ahead of print]

Interferon-γ causes myogenic cell dysfunction and senescence in immune myopathies.

Cyrielle Hou, Baptiste Periou, Marianne Gervais, Ludovic Martin, Juliette Berthier, Yasmine Baba-Amer, Sarah Souvannanorath, Emmanuele Lechapt-Zalcman, Edoardo Malfatti, Romain K Gherardi, Fréderic Relaix, Maximilien Bencze, François Jérôme Authier.

Idiopathic immune myopathies (IIM) represent a heterogeneous group of diseases, in which muscle lesions result from deregulated immune reactions. Typical histological features include myofibre necrosis, leukocyte infiltration, and aberrant myofibre Major Histocompatibility Complex (MHC) expression. To investigate the link between MHC expression, inflammation, and muscle lesions, muscle biopsies from IIM patients were analysed by transcriptomics. Both, anti-synthetase syndrome (ASS) and inclusion body myositis (IBM) displayed the upregulation of IFNγ and senescence signalling pathways. Notably, IFNγ expression significantly correlated with myofibre atrophy in ASS and IBM muscle biopsies. In addition to MHC-II expression at the myofibre sarcolemma in IBM, we observed a marked overexpression in the muscle stem cells (MuSC) population, suggesting that resident satellite cells respond to IFNγ in this condition. To examine the link between IFNγ and muscle atrophy via MuSCs, we implanted an osmotic pump chronically releasing recombinant mouse IFNγ in wild-type mice subjected to acute muscle injury. Under IFNγ exposure, post-injury muscle repair was associated with significantly reduced muscle weight and myofibre diameter, while promoting interstitial fibrosis and fat deposition. The mechanism of action of the IFNγ-induced myofibre atrophy was further investigated in vitro using cultured human MuSCs. IFNγ stimulation dramatically impaired MuSCs proliferation, fusion, and promoted cell senescence. Isolated myofibres from IFNγ-treated wild-type mice displayed a significant decrease of MyoD expression and cell cycling, suggesting that IFNγ also prevents MuSC activation. In vitro, ruxolitinib, a commercially available JAK1/2 antagonist, blocked IFNγ-induced expression of MHC-II, restored normal MuSC proliferation, and reduced β-Galactosidase activity, a marker of cell senescence. In vivo, oral delivery of ruxolitinib improved myofibre size and biomarkers of muscle atrophy. Our study provides multiple lines of evidence that IFNγ may mediate muscle atrophy in IBM patients. The identified mechanism of action involves JAK1/2 pathways, which impair MuSC function by preventing post-lesion myogenesis and promoting cell senescence. Our data suggest that repurposing JAK1/2 inhibitors may offer a new therapeutic option for treating IBM, a condition known for its resistance to classical immunosuppressant drugs, despite their effectiveness in other IIM.

Keywords: IFNγ; JAK-STAT; inclusion body myositis (IBM); inflammatory myopathies; myogenesis; satellite cells

DOI: https://doi.org/10.1093/brain/awaf153