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Summary: Somatic stem cells expand massively during tissue regeneration, which might require control of cell fitness, allowing elimination of non-competitive, potentially harmful cells. How or if such cells are removed to restore organ function is not fully understood. Here, we show that a substantial fraction of muscle stem cells (MuSCs) undergo necroptosis because of epigenetic rewiring during chronic skeletal muscle regeneration, which is required for efficient regeneration of dystrophic muscles. Inhibition of necroptosis strongly enhances suppression of MuSC expansion in a non-cell-autonomous manner. Prevention of necroptosis in MuSCs of healthy muscles is mediated by the chromatin remodeler CHD4, which directly represses the necroptotic effector Ripk3, while CHD4-dependent Ripk3 repression is dramatically attenuated in dystrophic muscles. Loss of Ripk3 repression by inactivation of Chd4 causes massive necroptosis of MuSCs, abolishing regeneration. Our study demonstrates how programmed cell death in MuSCs is tightly controlled to achieve optimal tissue regeneration.

Background: Nutritional muscle dystrophy is associated with selenium (Se) deficiency; however, the underlying mechanism remains unclear., Objectives: This study aimed to understand the crosstalk among redox status, energy metabolism, and inflammation in nutritional muscle dystrophy induced by dietary Se deficiency., Methods: Eighteen castrated male pigs (Yorkshire, 45 d old) were fed Se-deficient (Se-D; 0.007 mg Se/kg) or Se-adequate (Se-A; in the form of selenomethionine, 0.3 mg Se/kg) diets for 16 wk. The muscle Se concentrations; antioxidant capacity; and gene expression, transcriptome, global proteome, metabolome, and lipidome profiles were analyzed. The transcriptome, metabolome, and proteome profiles were analyzed with biostatistics, bioinformatics, and pathway enrichment analysis; other data were analyzed with Student's 2-sided t tests., Results: The muscle Se content in the Se-D group was 96% lower than that in the Se-A group (P < 0.05). The activity of glutathione peroxidase (GPX) and thioredoxin reductase (TXNRD) in the Se-D group was 42%-69% lower than that in the Se-A group (P < 0.05). The mRNA levels of 10 selenoprotein genes were 25%-84% lower than those in the Se-A group (P < 0.05). Multi-omics analyses indicated that the levels of 1378 transcripts, 83 proteins, 22 metabolites, and 55 lipid molecules were significantly altered in response to Se deficiency. Se deficiency-induced redox imbalance led to muscle central carbon and lipid metabolism reprogramming, which enhanced the glycolysis pathway and decreased phospholipid synthesis. Inflammation and apoptosis were observed in response to Se deficiency-induced muscle oxidative stress, which may have been associated with extracellular matrix (ECM) remodeling, suppressed focal adhesion and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, and activation of the NF-κB signaling pathway., Conclusions: These results contributed to understanding the crosstalk among redox, energy metabolism, and inflammation in Se deficiency-induced muscle dystrophy in pigs, and may provide intervention targets for muscle disease treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Duchenne muscular dystrophy (DMD) is characterized by a severe and progressive destruction of muscle fibers associated with altered Ca 2+ homeostasis. We have previously shown that the IP 3 receptor (IP 3 R) plays a role in elevating basal cytoplasmic Ca 2+ and that pharmacological blockade of IP 3 R restores muscle function. Moreover, we have shown that the IP 3 R pathway negatively regulates autophagy by controlling mitochondrial Ca 2+ levels. Nevertheless, it remains unclear whether IP 3 R is involved in abnormal mitochondrial Ca 2+ levels, mitochondrial dynamics, or autophagy and mitophagy observed in adult DMD skeletal muscle. Here, we show that the elevated basal autophagy and autophagic flux levels were normalized when IP 3 R was downregulated in mdx fibers. Pharmacological blockade of IP 3 R in mdx fibers restored both increased mitochondrial Ca 2+ levels and mitochondrial membrane potential under resting conditions. Interestingly, mdx mitochondria changed from a fission to an elongated state after IP 3 R knockdown, and the elevated mitophagy levels in mdx fibers were normalized. To our knowledge, this is the first study associating IP 3 R1 activity with changes in autophagy, mitochondrial Ca 2+ levels, mitochondrial membrane potential, mitochondrial dynamics, and mitophagy in adult mouse skeletal muscle. Moreover, these results suggest that increased IP 3 R activity in mdx fibers plays an important role in the pathophysiology of DMD. Overall, these results lead us to propose the use of specific IP 3 R blockers as a new pharmacological treatment for DMD, given their ability to restore both autophagy/mitophagy and mitochondrial function., (Copyright © 2018. Published by Elsevier B.V.)

Objective: There is increasing evidence that an involvement of central nervous system (CNS) can occur in several myopathies. Transcranial magnetic stimulation (TMS) may represent a valuable tool for investigating important neurophysiological and pathophysiological aspects of cortical involvement in neuromuscular disorders. In this review paper we aimed to perform a systematic search of the studies employing TMS techniques in subjects suffering from myopathies., Methods: A literature search was conducted using PubMed and Embase. We identified and reviewed 9 articles matching the inclusion criteria. One hundred twenty patients were included in these studies, which have applied TMS in patients with muscle disorders., Results: To date, a few studies using TMS have been performed in myopathic patients and detected subclinical abnormalities in cortical reactivity and plasticity. The most consistent finding was a decrease in intracortical inhibition, which likely represents a non-specific compensatory mechanism of the CNS in an attempt to overcome the muscle deficit through an increase of the motor cortex output to deficient muscles., Conclusions: Application of TMS to characterize the pathophysiology of the CNS in these subjects appears to be safe and may lead to the development of valuable biomarkers. Well-defined motor cortical excitability patterns can be identified in the different muscle diseases, even if preliminary findings should be confirmed in future studies in larger cohorts of patients., Significance: TMS studies may shed new light on the physiological and pathophysiological mechanisms underlying the cortical involvement in muscle disorders., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)