PINK1 Deficiency Alters Muscle Stem Cell Fate Decision And Muscle Regenerative Capacity.

Abstract

Maintenance of optimal mitochondrial function plays a crucial role in the regulation of muscle stem cell (MuSC) behavior, but the underlying maintenance mechanisms remain ill defined. In this study, we explored the importance of mitophagy, as a mitochondrial quality control regulator, in MuSCs and the role this process plays in maintaining optimal muscle regenerative capacity. Here we show that MuSCs exhibit dynamic alterations in mitophagy under different physiological myogenic states. In particular, quiescent MuSCs exhibit high levels of PINK1/Parkin-dependent mitophagy, which is rapidly decreased upon transition to an early activation state. Genetic disruption of this pathway using Pink1 knockout mice reduced mitophagy in quiescent MuSCs, which was accompanied by increased mitochondrial ROS release and mitochondrial network fragmentation. These abnormalities led to hampered self-renewal of MuSCs which ultimately translated in a progressive loss of muscle regeneration following repetitive injury. However, proliferation and differentiation capacity were unaltered in the absence of PINK1, indicating that altered fate decisions is the main mechanism underlying impaired muscle regeneration. Impaired fate decisions in PINK1 deficient MuSCs could be restored by scavenging excess mitochondrial ROS. Together, these data shed new light on the regulation of mitophagy during MuSC state transitions and position the PINK1-dependent pathway as an important regulator of MuSC mitochondrial properties and fate decisions.