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Satellite cells are the chief contributor to skeletal muscle growth and regeneration. The study of mouse satellite cells has accelerated in recent years due to technical advancements in the isolation of these cells. The study of human satellite cells has lagged and thus little is known about how the biology of mouse and human satellite cells compare. We developed a flow cytometry-based method to prospectively isolate human skeletal muscle progenitors from the satellite cell pool using positive and negative selection markers. Results show that this pool is enriched in PAX7 expressing cells that possess robust myogenic potential including the ability to give rise to de novo muscle in vivo. We compared mouse and human satellite cells in culture and identify differences in the elaboration of the myogenic genetic program and in the sensitivity of the cells to cytokine stimulation. These results indicate that not all mechanisms regulating mouse satellite cell activation are conserved in human satellite cells and that such differences may impact the clinical translation of therapeutics validated in mouse models. Thus, the findings of this study are relevant to developing therapies to combat muscle disease.

Nicotinamide adenine dinucleotide (NAD+) is a key cofactor required for essential metabolic oxidation-reduction reactions. It also regulates various cellular activities, including gene expression, signaling, DNA repair and calcium homeostasis. Intracellular NAD+ levels are tightly regulated and often respond rapidly to nutritional and environmental changes. Numerous studies indicate that elevating NAD+ may be therapeutically beneficial in the context of numerous diseases. However, the role of NAD+ on skeletal muscle exercise performance is poorly understood. CD38, a multi-functional membrane receptor and enzyme, consumes NAD+ to generate products such as cyclic-ADP-ribose. CD38 knockout mice show elevated tissue and blood NAD+ level. Chronic feeding of high-fat, high-sucrose diet to wild type mice leads to exercise intolerance and reduced metabolic flexibility. Loss of CD38 by genetic mutation protects mice from diet-induced metabolic deficit. These animal model results suggest that elevation of tissue NAD+ through genetic ablation of CD38 can profoundly alter energy homeostasis in animals that are maintained on a calorically-excessive Western diet.