Rethinking Muscle Aging Through the Lens of Fibro-Adipogenic Progenitors.

Aging of skeletal muscles is accompanied by a progressive deposition of adipose and fibrotic tissue within the interstitial compartment. This process profoundly disrupts the structural integrity and contractile function of the muscle.

Such maladaptive remodeling not only compromises muscle performance but also impairs its regenerative capacity, predisposing old individuals to frailty and sarcopenia. Fibro-adipogenic progenitors (FAPs) have been identified as the principal cellular source of the pathological adipogenic and fibrogenic remodeling.

These stromal cells integrate mechanical, biochemical, and immune signals within the muscle niche, ultimately determining whether muscle repair leads to effective regeneration or maladaptive remodeling. In young muscle, transient FAP activation supports satellite cell-mediated myogenesis through extracellular matrix remodeling and pro-regenerative signaling.

However, in aging muscle, this precise regulation is disrupted. The aged niche is characterized by chronic inflammatory stress, altered matrix composition, and impaired immune-stromal communication.

These changes drive FAPs toward maladaptive phenotypes that promote fibrosis, intramuscular fat accumulation, and regenerative failure. FAP dysfunction is increasingly recognized as a central mechanism contributing to age-related sarcopenia, increased susceptibility to injury, and delayed recovery.

Given their dual ability to promote both regeneration and degeneration, understanding how aging reprograms FAP fate and function offers a promising avenue to rejuvenating the aged muscle niche. Here, we summarize current insights into the roles and dynamics of FAPs in aged muscle and discusses their potential as therapeutic targets to restore regenerative capacity and mitigating muscle aging.