Sarcopenia, the progressive loss of skeletal muscle mass and function with aging, is a major challenge to healthy longevity due to its profound effects on mobility, metabolism, and overall health. In addition to locomotion, skeletal muscles regulate glucose homeostasis and secrete signaling molecules known as myokines, which influence cognition, cardiovascular function, and immunity. Therefore, preservation of muscle homeostasis is essential for prolonged health span. Age-related muscle decline involves reduced muscle mass and alterations in myofiber composition, which compromises the contractile performance. Myofibers are broadly categorized into slow type I and fast type II fibers; type II fibers are further classified into IIa, IIx, and IIb fibers based on their myosin heavy chain isoforms. Recent studies have identified large Maf transcription factors (Mafa, Mafb, and Maf) as principal regulators of type IIb myofiber formation in mice. Notably, large Mafs reactivate the normally silent type IIb myofiber program in human muscles and show strong associations with fast type II myofiber composition in human muscle biopsies. However, whether high Maf activity can be harnessed to counteract the preferential loss of fast type II myofibers in aging muscles remains unknown. Although therapeutic applications remain limited, elucidation of the transcriptional mechanisms governing myofiber type determination will provide a critical framework to address the open questions related to muscle biology, aging, and human performance. In this review, we discuss both established and emerging regulators of myofiber type, particularly focusing on large Mafs, and highlight the recent advances that have reshaped our understanding of muscle plasticity.
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