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A mitofusin 2/HIF1α axis sets a maturation checkpoint in regenerating skeletal muscle
We report the existence of a maturation checkpoint during muscle regeneration that pauses myofibers at a neonatal stage. This checkpoint is regulated by the mitochondrial protein mitofusin 2 (Mfn2), the expression of which is activated in response to muscle injury. Mfn2 is required for growth and maturation of regenerating myofibers; in the absence of Mfn2, new myofibers arrested at a neonatal stage, characterized by centrally nucleated myofibers and loss of H3K27me3 repressive marks at the neonatal myosin heavy chain gene. A similar arrest at the neonatal stage was observed in infantile cases of human centronuclear myopat...
Source: Journal of Clinical Investigation - December 1, 2022 Category: Biomedical Science Authors: Xun Wang, Yuemeng Jia, Jiawei Zhao, Nicholas P. Lesner, Cameron J. Menezes, Spencer D. Shelton, Siva Sai Krishna Venigalla, Jian Xu, Chunyu Cai, Prashant Mishra Source Type: research

Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium
Troponin C (TnC) is a critical regulator of skeletal muscle contraction; it binds Ca2+ to activate muscle contraction. Surprisingly, the gene encoding fast skeletal TnC (TNNC2) has not yet been implicated in muscle disease. Here, we report 2 families with pathogenic variants in TNNC2. Patients present with a distinct, dominantly inherited congenital muscle disease. Molecular dynamics simulations suggested that the pathomechanisms by which the variants cause muscle disease include disruption of the binding sites for Ca2+ and for troponin I. In line with these findings, physiological studies in myofibers isolated from patien...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Martijn van de Locht, Sandra Donkervoort, Josine M. de Winter, Stefan Conijn, Leon Begthel, Benno Kusters, Payam Mohassel, Ying Hu, Livija Medne, Colin Quinn, Steven A. Moore, A. Reghan Foley, Gwimoon Seo, Darren T. Hwee, Fady I. Malik, Thomas Irving, Wei Source Type: research

Autoantibodies targeting TRIM72 compromise membrane repair and contribute to inflammatory myopathy
Idiopathic inflammatory myopathies (IIM) involve chronic inflammation of skeletal muscle and subsequent muscle degeneration due to an uncontrolled autoimmune response; however, the mechanisms leading to pathogenesis are not well understood. A compromised sarcolemmal repair process could promote an aberrant exposure of intramuscular antigens with the subsequent initiation of an inflammatory response that contributes to IIM. Using an adoptive transfer mouse model of IIM, we show that sarcolemmal repair is significantly compromised in distal skeletal muscle in the absence of inflammation. We identified autoantibodies against ...
Source: Journal of Clinical Investigation - July 21, 2020 Category: Biomedical Science Authors: Kevin E. McElhanon, Nicholas Young, Jeffrey Hampton, Brian J. Paleo, Thomas A. Kwiatkowski, Eric X Beck, Ana Capati, Kyle Jablonski, Travis Gurney, Miguel A. Lopez Perez, Rohit Aggarwal, Chester V. Oddis, Wael N. Jarjour, Noah Weisleder Source Type: research