Metabolic Regulation by p107 (Rbl1) Influences Muscle Stem Cell Fate Decisions

Skeletal muscle has a remarkable property of effective muscle fiber regeneration that maintain their normal physiology due to the presence of the adult muscle stem cells known as the satellite cells (SCs). The role of SCs is crucial, as myofiber turnover is an ongoing process during the lifetime of an individual to maintain proper muscle tissue viability. However, muscle wasting found in diseases such as muscular dystrophy and disorders that occur during the ageing process are associated with impaired SC function. Indeed, these complications are linked to compromised SC fate decisions for activation, self-renewal and commitment to muscle progenitor cells (MPs), which are characterized by diminished numbers. Thus, understanding the control pathways that impact SC fates is essential to improve their integrity for health and to benefit muscle diseases and disorders. Central to sustaining different SC fates is the regulation of energy generation between glycolysis in the cytoplasm and oxidative phosphorylation (Oxphos) in the mitochondria. However, the mechanisms that connect these energy provisioning centers to control cell behaviour remain obscure. Herein, our results reveal a mechanism by which mitochondrial-localized transcriptional co-repressor p107 governs MP proliferative rate, under the control of NAD+/NADH ratio. We found p107 directly interacts at the mitochondrial DNA promoter repressing mitochondrial-encoded genes. This reduces the mitochondrial ATP generation capacity, by limiting the electron transport chain complex formation. Importantly, the amount of ATP generated by the mitochondrial function of p107 is directly associated to the cell cycle rate in vivo and in vitro. This is exemplified by absence of p107 that drastically increased cell cycle progression and MP proliferation capacity through enhancement of ATP generation. Oppositely, forced expression of p107 in the mitochondria blocked cell cycle progression in vitro as a consequence of dampened ATP generation. Notably, Sirt1, whose activity is dependent on the cytoplasmic by-product of glycolysis, NAD+, directly interacts with p107 impeding its mitochondrial localization and function. Deletion of Sirt1 increased p107 mitochondrial localization, decreased MP mitochondrial Oxphos generation concomitant with attenuated cell cycle progression. Increasing the activity of Sirt1 had the converse effect on p107 function. In addition, we also showed that p107 genetically deleted skeletal muscle contained significantly more quiescent SCs, indicative of a better self-renewal ability. As a first step to test the physiological role of p107 on SCs and MPs, we assessed exercise in humans. We found p107 protein levels were inversely correlated with enhanced mitochondrial Oxphos following endurance exercise in skeletal muscle that might also occur in SCs. These novel results establish a new paradigm to manipulate muscle stem cell fate decisions that are impaired in many diseases and disorders.