Investigating the Therapeutic Potential of Altering Drp1 Expression to Counter Sarcopenia

Abstract

Rationale The aging-related loss of skeletal muscle mass and function, or sarcopenia, is a debilitating process dramatically impairing the quality of life of afflicted individuals. Although the mechanisms underlying sarcopenia are still only partly understood, impairments in mitochondrial dynamics, and notably in mitochondrial fission, have been proposed as an underlying mechanism. Importantly, conflicting data exist in the field and both excessive and insufficient mitochondrial fission were proposed to contribute to sarcopenia. Interestingly, promoting mitochondrial fission in midlife through Drp1 overexpression was recently shown to extend lifespan and attenuate several key hallmarks of muscle aging in flies. However, to date, whether modulating mitochondrial fission can impact the muscle aging process in mammals has never been investigated. Objective To define whether altering Drp1 expression in skeletal muscles of late middle-aged mice can impact the muscle aging process. Methods Drp1 expression was knocked down or overexpressed for 4 months in the gastrocnemius and tibialisanterior muscles of 18 months-old C57BL/6J mice using intramuscular injections of Adeno-Associated Viruses (AAVs). Results Drp1 knockdown in middle-aged mice resulted in severe muscle atrophy (-35 to 52%). Drp1 overexpression also resulted in muscle atrophy, although to a milder extend (-9%). Drp1 knockdown resulted in reduced mitochondrial respiration coupled with an increase in mitochondrial content. Drp1 overexpression did not impact maximal mitochondrial respiration but increased the content of proteins involved in the oxidative phosphorylation, indicating altered mitochondrial quality. Neither Drp1 overexpression nor Drp1 knockdown altered mitochondrial H2O2emission. Drp1 knockdown, but not Drp1 overexpression, resulted in an increase in markers of oxidative stress, muscle degeneration and impaired autophagy. Conclusions Taken altogether, our results indicate that both overexpressing and silencing Drp1 late in life negatively impact skeletal muscles and their mitochondria. These results highlight that Drp1 content must be remain within a fairly narrow physiological range to preserve muscle and mitochondrial integrity during aging. Our results finally emphasize that altering Drp1 expression is unlikely to be a viable target to counter sarcopenia.