<p>Insulin-like growth factors (IGFs) are key regulators of the stem cell niche, playing critical roles in the proliferation and differentiation of stem cells into various lineages, including skeletal muscle. While IGF2 is known to influence muscle development, its specific effects and mechanisms in human skeletal muscle remain incompletely understood. In this study, we demonstrate that IGF2 is a key regulator of human satellite cell (huSC) proliferation, differentiation, and mitochondrial bioenergetics. Using primary huSCs cultured under defined myogenic conditions, we show that IGF2 significantly enhances myoblast proliferation and promotes differentiation via upregulation of myogenic regulatory factors and activation of the IGF1 receptor (IGF1R) pathway. Knockdown of endogenous IGF2 impaired these processes, while exogenous supplementation restored myogenic potential. Notably, IGF2 also improved mitochondrial function, evidenced by increased oxygen consumption rate, mitochondrial mass, oxidative phosphorylation protein expression, and intracellular ATP production. These effects were primarily mediated through IGF1R signaling, with IGF2R playing a modulatory role in regulating IGF2 availability. Our findings reveal that IGF2 not only initiates structural differentiation but also drives metabolic reprogramming in huSCs, highlighting its dual role in supporting muscle regeneration and energy homeostasis. These insights highlight IGF2 as a promising therapeutic target for muscle-wasting conditions such as muscular dystrophy and age-related sarcopenia and suggest its broader potential in regenerative medicine strategies.</p>