Collectively, based on the analyses of data obtained using cell culture and in vivo mouse modeling under different conditions, we infer that the p16Ink4a-Cdk4-E2F3 signals (a) differentially affect myoblast proliferation and its regeneration potential (based on the CTX injury model) and, (b) upon differentiation, these signals selectively regulate the expression of specific muscle fiber–type markers and muscle mitochondrial genes. The gene discussed is E2F3; the disease is cerebrotendinous xanthomatosis.