Drp1 knockdown induces severe muscle atrophy and remodelling, mitochondrial dysfunction, autophagy impairment and denervation

Abstract

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.

Keywords: fibrosis; mitochondrial dynamics; mitochondrial fission; myopathic phenotype; neuromuscular junction; oxidative stress; skeletal muscle atrophy.