bims-musmir 2025-04-06 papers

Sci Adv. 2025 Apr 04. 11(14): eadt4955

Neural stimulation suppresses mTORC1-mediated protein synthesis in skeletal muscle.

Ana G Dumitras, Giorgia Piccoli, Frederik Tellkamp, Lena Keufgens, Martina Baraldo, Sabrina Zorzato, Laura Cussonneau, Leonardo Nogara, Marcus Krüger, Bert Blaauw.

Skeletal muscle fibers are classified as glycolytic or oxidative, with differing susceptibilities to muscle wasting. However, the intracellular signaling pathways regulating fiber-specific muscle trophism remain unclear because of a lack of experimental models measuring protein synthesis. We developed a mouse model overexpressing a mutated transfer RNA synthetase in muscle fibers, enabling specific protein labeling using an artificial methionine substitute, which can be revealed through click chemistry. This model revealed that denervation increases protein labeling in oxidative muscle fibers through mammalian target of rapamycin complex 1 (mTORC1) activation, while deleting the mTORC1 scaffold protein Raptor reduces labeling in glycolytic fibers. On the other hand, increased muscle activity acutely decreases protein synthesis, accompanied by reduced mTORC1 signaling, glycogen depletion, and adenosine 5'-monophosphate kinase activation. Our findings identify nerve activity as an inhibitory signal for mTORC1-dependent protein synthesis in skeletal muscle, enhancing the understanding of fiber-specific responses to exercise and pathological conditions.

DOI: https://doi.org/10.1126/sciadv.adt4955

Neuropathol Appl Neurobiol. 2025 Apr;51(2): e70014

Computational Analysis of SOD1-G93A Mouse Muscle Biomarkers for Comprehensive Assessment of ALS Progression.

Pedro Gómez-Gálvez, Victoria Navarro, Ana M Castro, Carmen Paradas, Luis M Escudero.

AIMS: To identify potential image biomarkers of neuromuscular disease by analysing morphological and network-derived features in skeletal muscle biopsies from a murine model of amyotrophic lateral sclerosis (ALS), the SOD1G93A mouse and wild-type (WT) controls at distinct stages of disease progression.
METHODS: Using the NDICIA computational framework, we quantitatively evaluated histological differences between skeletal muscle biopsies from SOD1G93A and WT mice. The process involved the selection of a subset of features revealing these differences. A subset of discriminative features was selected to characterise these differences, and their temporal dynamics were assessed across disease stages.
RESULTS: Our findings demonstrate that muscle pathology in the mutant model evolves from early alterations in muscle fibre arrangement, detectable at the presymptomatic stage through graph theory features, to the subsequent development of the typical morphological pattern of neurogenic atrophy at more advanced disease stages.
CONCLUSIONS: Our assay identifies a neurogenic signature in mutant muscle biopsies, even when the disease is phenotypically imperceptible.

Keywords: SOD1‐G93A; amyotrophic lateral sclerosis; graph theory; image analysis; image biomarker; motor neuron degeneration

DOI: https://doi.org/10.1111/nan.70014

Exp Physiol. 2025 Mar 30.

Muscle wasting in cancer cachexia: Mechanisms and the role of exercise.

Zoe P Libramento, Louisa Tichy, Traci L Parry.

Cancer cachexia (CC) is a multifactorial disease marked by a severe and progressive loss of lean muscle mass and characterized further by inflammation and a negative energy/protein balance, ultimately leading to muscle atrophy and loss of muscle tissue. As a result, patients experiencing cachexia have reduced muscle function and thus less independence and a lower quality of life. CC progresses through stages of increasing severity: pre-cachexia, cachexia and refractory cachexia. Two proposed underlying mechanisms that drive cancer-induced muscle wasting are the autophagy-lysosome and ubiquitin-proteasome systems. An increase in autophagic flux and proteolytic activity leads to atrophy of both cardiac and skeletal muscle, ultimately mediated by tumour or immune-secreted inflammatory cytokines. These pathways occur at a basal level to maintain cellular homeostasis; therefore, it is the overactivation of the pathways that leads to muscle atrophy. Recent evidence demonstrates the ability of aerobic and resistance training to restore these pathways to their basal levels. The mechanism is not yet understood, and more research is needed to determine exactly how exercise influences each pathway. However, exercise has great promise as a therapeutic strategy for CC because of the evidence for it preserving muscle mass and function, and attenuating protein degradative pathways. The extent to which exercise affects the ubiquitin-proteasome and autophagy-lysosome systems is determined by the frequency, intensity and duration of the exercise protocol. As such, an ideal exercise prescription is lacking for individuals with CC.

Keywords: atrophy; cancer cachexia; exercise

DOI: https://doi.org/10.1113/EP092544

Nat Commun. 2025 Apr 03. 16(1): 3190

Muscle fiber Myc is dispensable for muscle growth and its forced expression severely perturbs homeostasis.

Daniel J Ham, Michelangelo Semeraro, Bianca M Berger, Timothy J McGowan, Shuo Lin, Eleonora Maino, Filippo Oliveri, Markus A Rüegg.

The oncogenic transcription factor Myc stimulates many growth processes including cell cycle progression and ribosome biogenesis. Myc expression is low in adult skeletal muscle, but is upregulated upon growth stimuli. Furthermore, muscle fiber Myc overexpression recapitulates many aspects of growth-related gene expression, leading to the hypothesis that Myc mediates pro-growth responses to anabolic stimuli, such as exercise. Here, we test this hypothesis by examining mouse models in which Myc is specifically eliminated or overexpressed in skeletal muscle fibers or muscle stem cells (MuSC). While muscle fiber Myc expression increased during muscle growth and Myc expression in MuSCs was required for successful muscle regeneration, muscle fiber Myc expression was dispensable for post-natal, mechanical overload or PKBα/Akt1-induced muscle growth in mice. Similarly, constitutive Myc expression did not promote skeletal muscle hypertrophy, but instead impaired muscle fiber structure and function within days. These data question the role of Myc in skeletal muscle growth.

DOI: https://doi.org/10.1038/s41467-025-58542-7

Sci Rep. 2025 Apr 03. 15(1): 11460

Increased fat accumulation may be associated with severe muscle wasting in critically ill patients: a prospective observational study.

Yasutaka Koga, Motoki Fujita, Kayoko Harada, Masaru Shin, Ryo Ayata, Tomoaki Inoue, Kotaro Kaneda, Ryosuke Tsuruta.

Obesity has been hypothesized to attenuate muscle wasting in critically ill patients due to increased ketogenesis. This study examined the associations between fat mass volume, ketone bodies, and muscle wasting in critically ill patients. We conducted a prospective study in an emergency intensive care unit (ICU) from November 2021 to October 2023, enrolling adult patients with an expected ICU stay of ≥ 7 days and abdominal computed tomography (CT) performed within 24 h of admission. Patients were classified as adipose or lean based on fat area measured via CT. The primary outcome was severe muscle wasting, defined as a > 10% decrease in the rectus femoris cross-sectional area measured by ultrasonography from day 1 to day 7. Among 134 enrolled patients, 108 were evaluable (57% male, median age 73 years). Severe muscle wasting was more frequent in the adipose group (48%) than in the lean group (27%, p = 0.023). Multivariate analysis confirmed a higher risk of muscle wasting in the adipose group (adjusted OR 2.52, p = 0.034). BHB levels were inversely correlated with fat area and associated with a reduced risk of muscle wasting. Contrary to our hypothesis, obesity increased the risk of muscle wasting, potentially due to decreased ketogenesis.200/200 words.

Keywords: ICU-acquired weakness; Ketone body; Muscle wasting; Obesity

DOI: https://doi.org/10.1038/s41598-025-96171-8

Eur J Intern Med. 2025 Apr 01. pii: S0953-6205(25)00128-1. [Epub ahead of print]

Differential modulations of miRNAs in patients with systemic sclerosis-associated skeletal muscle loss.

Federica Tambaro, Antonietta Gigante, Carmen Gallicchio, Chiara Pellicano, Cesarina Ramaccini, Roberta Belli, Maria Ludovica Gasperini-Zacco, Edoardo Rosato, Maurizio Muscaritoli.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by sustained vascular inflammation and progressive skin and internal organs fibrosis. Up to 22 % of SSc patients may manifest skeletal muscle impairment, which predicts worse clinical outcomes, including increased mortality, however, pathogenesis is still largely unclear and could be associated with modulation of circulating microRNAs (miRNAs). Aims of the present study were to evaluate differentially modulated miRNAs in SSc patients and to evaluate their association with changes in body composition(s) and with the clinical course and type of the disease.
METHODS: Circulating levels of miRNAs were detected by RT-qPCR. ELISA assay was performed to measure the TGF-β1 protein. Muscularity (FFMI kg/m2) and phase angle (PhA, °) were estimated by Bioelectrical Impedance Analysis.
RESULTS: We enrolled 47 SSc patients and 21 controls (C). We observed downregulation of miR-15b (p = 0.024), -21 (p < 0.001), -29a (p < 0.001), -29b (p = 0.007) and -133a (p < 0.001), whereas miR-206 (p < 0.001) and -486 (p < 0.001) were upregulated in SSc vs C. In SSc, miR-29b negatively correlates with TGF-β1 (r = -0.303, p = 0.046). MiR-206 was downregulated vs high FFMI (p = 0.040) in SSc with low FFMI, and miR-15b positively correlates with PhA (r = 0.356, p = 0.014). MiR-15b and -486 were modulated in early vs late nailfold capillaroscopy stage (p = 0.028 and p = 0.045, respectively). MiR-133a was higher in SSc with Scl70 v ACA subset of autoantibodies (p = 0.002).
CONCLUSIONS: In SSc patients, differential modulations of miRNAs involved in muscularity occur. The data obtained suggest that mechanisms other than disease-related malnutrition might be responsible for SSc-associated skeletal muscle loss.

Keywords: Low muscularity; Micrornas; Muscle depletion; Sarcopenia; Systemic sclerosis

DOI: https://doi.org/10.1016/j.ejim.2025.03.034