Feb 15, 2020

PDH Mediated Mitochondrial Respiration Controls the Speed of Muscle Stem Cell Activation in Muscle Repair and Aging

BioRxiv : the Preprint Server for Biology
Manmeet H. RavalJoseph T. Rodgers

Abstract

Decline in the skeletal muscle stem cell (MuSC) function is a major contributor to age-associated impairments in muscle regeneration and function. The ability of MuSCs to activate (i.e. exit quiescence, enter the cell cycle, and divide) following injury is a critical step that initiates muscle regeneration. However, the mechanisms that regulate MuSC activation function are poorly understood. Here, we show that the activation function, specifically the speed by which cells progress through G0-G1, declines tremendously with age in mouse MuSCs. Using a number of in vivo models and ex vivo assays of MuSC activation and muscle regenerative functions, live cell metabolic flux analyses, and metabolomics we present data indicating that changes in MuSC mitochondrial flux underlie age-associated changes in MuSC activation. We show that, in the course of MuSC activation, there is a profound,16-fold, increase in ATP production rates, which is fueled largely by increases in pyruvate flux into mitochondria. We found that MuSCs from aged mice display progressive defects in the ability to increase mitochondrial flux during activation and that this correlates with higher levels of phosphorylated, inactivated, pyruvate dehydrogenase (PDH). Impor...Continue Reading

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Mentioned in this Paper

Pyruvate Oxidation
Beta-PDH
Natural Regeneration
Mitochondria
Pyruvate dehydrogenase
Mitochondrial Inheritance
Muscle
Cell Cycle
Respiration
Adenosine Triphosphate

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