Extrinsic Regulation of Satellite Cell Function and Muscle Regeneration Capacity during Aging

Optimal regeneration of skeletal muscle in response to injury requires the contribution of tissue resident stem cells termed satellite cells. Normally residing at the interface between the muscle fiber and overlying basal lamina it is generally understood with age the satellite cell pool exhibits decline both in number and function. Over the past decade mechanisms that contribute to these declines have begun to emerge. Implicit in aged-related satellite cell dysfunction and decline is the involvement of signals from the environment. Many of the signals that become deregulated with age have conserved functions during distinct stages of muscle fiber formation both in early development and regeneration. In particular, modulations in Wnt, TGFβ, Notch and FGF emanating from aged skeletal muscle fibers or the systemic milieu have emerged as age-related alterations that significantly impact both the maintenance of the satellite cell pool and skeletal muscle regenerative efficacy. In this review we will summarize how the aforementioned pathways contribute to skeletal muscle development and regeneration. We will then discuss deregulation of these cascades with age and how they contribute to satellite cell depletion and dysfunction. The review will also summarize some of the challenges we face in trying to draw parallels between murine and human satellite cell aging. Finally, we will highlight the few examples whereby FDA approved drugs may be exploited to modulate specific signaling cascades in effort to preserve skeletal muscle regenerative function with age.