Disuse-associated loss of the protease LONP1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength

Abstract

Mitochondrial proteolysis is an evolutionarily conserved quality-control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a role in controlling mitochondrial function as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related muscle loss is associated with decreased mitochondrial LONP1 protein. Skeletal muscle-specific ablation of LONP1 in mice resulted in impaired mitochondrial protein turnover, leading to mitochondrial dysfunction. This caused reduced muscle fiber size and strength. Mechanistically, aberrant accumulation of mitochondrial-retained protein in muscle upon loss of LONP1 induces the activation of autophagy-lysosome degradation program of muscle loss. Overexpressing a mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC), a known protein degraded by LONP1, in skeletal muscle induces mitochondrial dysfunction, autophagy activation, and cause muscle loss and weakness. Thus, these findings reveal a role of LONP1-dependent mitochondrial protein quality-control in safeguarding mitochondrial function and preserving skeletal muscle mass and strength, and unravel a link between mitochondrial protein quality and muscle mass maintenance during muscle disuse.

Mitochondrial proteostasis stress in muscle drives a long-range protective response to alleviate dietary obesity independently of ATF4

“…LONP1 resides in the mitochondrial matrix and is the most conserved mitochondrial protease from yeast to humans ( 1 , 4 ). We recently generated skeletal muscle–specific Lonp1 -knockout (LONP1 mKO) mice ( 32 ), and we examined the consequences of LONP1 loss of function on muscle mitochondrial proteostasis by breeding LONP1 mKO mice with MitoTimer reporter mice. As shown in Fig.…”

“…We next evaluated how LONP1 mKO mice could adapt to HFD metabolic stress. Although LONP1 mKO mice were smaller and showed reduced muscle mass ( 32 ), we followed a cohort of LONP1 mKO mice that show survival similar to that of respective WT littermates at least up to 1.5 years of age. LONP1 mKO mice were also leaner when fed standard chow diet (CD) and were resistant to obesity on HFD, gaining body weight similarly to WT mice on CD ( Fig.…”

“…Moreover, we show that functionally, loss of muscle LONP1 triggers extensive metabolic reprogramming in skeletal muscle and protects the mice from diet-induced obesity. Notably, we have recently demonstrated that LONP1 deficiency activates autophagy-lysosome degradation program of muscle loss, resulting in reduced skeletal muscle mass and strength in particular during muscle disuse ( 32 ). Total lean mass was equivalently reduced in LONP1 mKO mice regardless of the diet; thus, the reduced body weight in HFD-fed LONP1 mKO mice can be attributed to both reduced fat mass and lean mass.…”

“…Samples were sectioned using a Leica EM UC7 and placed on copper grids. Images were taken on an FEI Tecnai G2 20 Twin electron microscope equipped with an Eagle 4k charge-coupled device digital camera (FEI; USA) in a double-blind manner ( 32 ).…”

“…We next evaluated how LONP1 mKO mice could adapt to HFD metabolic stress. Although LONP1 mKO mice were smaller and showed reduced muscle mass (32), we followed a cohort of LONP1 mKO mice that show survival similar to that of respective WT littermates at least up to 1.5 years of age.…”