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Drp1 knockdown induces severe muscle atrophy and remodelling, mitochondrial dysfunction, autophagy impairment and denervation
Author(s) -
Dulac Maude,
LeducGaudet JeanPhilippe,
Reynaud Olivier,
Ayoub MarieBelle,
Guérin Amanda,
Finkelchtein Michel,
Hussain Sabah NA,
Gouspillou Gilles
Publication year - 2020
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp279802
Subject(s) - mitochondrial fission , microbiology and biotechnology , skeletal muscle , mitochondrion , muscle atrophy , mitochondrial fusion , autophagy , biology , mitophagy , mitochondrial biogenesis , atrophy , gene knockdown , endocrinology , apoptosis , biochemistry , mitochondrial dna , genetics , gene
Key points The maintenance of optimal mitochondrial content and function is critical for muscle health. Mitochondrial dynamics play key roles in mitochondrial quality control; however, the exact role that mitochondrial fission plays in skeletal muscle health remains unclear. Here we report knocking down Drp1 (a protein regulating mitochondrial fission) for 4 months in adult mouse skeletal muscle resulted in severe muscle atrophy (40–50%). Drp1 knockdown also led to a reduction in ADP‐stimulated respiration, an increase in markers of impaired autophagy and increased muscle regeneration, denervation, fibrosis and oxidative stress. Our data indicate that Drp1 is crucial for the maintenance of normal mitochondrial function and that Drp1 depletion severely impairs muscle health.Abstract Mitochondria play central roles in skeletal muscle physiology, including energy supply, regulation of energy‐sensitive signalling pathways, reactive oxygen species production/signalling, calcium homeostasis and the regulation of apoptosis. The maintenance of optimal mitochondrial content and function is therefore critical for muscle cells. Mitochondria are now well known as highly dynamic organelles, able to change their morphology through fusion and fission processes. Solid experimental evidence indicates that mitochondrial dynamics play key roles in mitochondrial quality control, and alteration in the expression of proteins regulating mitochondrial dynamics have been reported in many conditions associated with muscle atrophy and wasting. However, the exact role that mitochondrial fission plays in skeletal muscle health remains unclear. To address this issue, we investigated the impact of Drp1 (a protein regulating mitochondrial fission) knockdown, introduced via intramuscular injection of adeno‐associated virus (AAV) on adult mouse skeletal muscle. Knocking down Drp1 for 4 months resulted in very severe muscle atrophy (40–50%). Drp1 knockdown also led to a reduction in ADP‐stimulated respiration and increases in markers of muscle regeneration, denervation, fibrosis, oxidative stress and impaired autophagy. Our findings indicate that Drp1 is essential for the maintenance of normal mitochondrial function and that Drp1 suppression severely impairs muscle health.