Maintenance of skeletal muscle (SkM) mass and strength throughout the lifespan is dependent on post-injury tissue regeneration, a process that is diminished with aging. Muscle-specific adult stem cells (MuSCs) and their committed progeny, muscle progenitor cells (MPCs), are required for SkM regeneration. After injury, MuSCs transition through a number of cell states, first they must activate from quiescence, giving rise to MPCs that undergo rapid proliferation prior to commitment to differentiation with a small number of MuSCs returning to quiescence. Using human and mouse models as well as immortalized cell lines this dissertation identifies novel regulators and requirements for MuSC state transitions and SkM regeneration. This dissertation identifies metabolism and mRNA modifications as central regulators of MuSC function and consequently SkM regeneration. First, expression of Peptide Tyrosine Tyrosine (PYY), a gut peptide implicated in post-prandial metabolism, was demonstrated in human SkM and MPCs. During proliferation, PYY expression was dynamic in young and old human derived MPCs and regulated by metabolic stress. Next, the non-essential amino acid serine was discovered as the only amino acid reduced in the aged human MuSC microenvironment. Availability of extracellular serine and the metabolically linked amino acid glycine were shown to be required for the synthesis of glutathione, and decreased serine/glycine concentrations were sensed in an EIF2_-dependent manner resulting in human MPC proliferation arrest, in vitro. Building on these findings, dietary restriction of serine/glycine in mice was shown to reduce MuSC abundance in young and aged mice, 3 days post injury (dpi), and to promote SkM fat infiltration 28 dpi in aged mice. The final chapter of this dissertation established that the most abundant internal mRNA modification, N6-methyladenosine (m6A), regulates MuSC/MPC state transitions. m6A-modification was greater during MPC proliferation (vs. differentiation) and m6A-specific sequencing (MeRIP-seq) revealed specific patterns of m6A-modified transcripts distinguishing proliferating and differentiating MPCs. Reducing m6A-modification abundance by methyltransferase-like 3 (METTL3) knockdown forced MPCs to prematurely differentiate in vitro and enhanced MuSC engraftment capacity after transplant. This dissertation demonstrates that nutrient availability (serine and glycine) and the expression of key proteins (PYY and METTL3) are integral in MPC/MuSC proliferation and subsequently SkM regeneration.