The extrinsic apoptotic pathway in aged skeletal muscle: Roles of tumor necrosis factor-alpha and interleukin-15.

摘要

Apoptosis is implicated in the loss of skeletal muscle mass following periods of reduced activity (i.e.-disuse) as well as during the normal aging process (i.e.-sarcopenia). Aging is also characterized by elevations in circulating cytokines, specifically TNF-alpha, which has been associated with the sarcopenic process. The specific signaling components that participate in the pro-apoptotic pathway downstream of the type I TNF receptor (i.e.-extrinsic apoptotic pathway) within skeletal muscle have not been clarified. Additionally, few studies have been performed with the aim of disrupting this apoptotic pathway, and thereby sparing muscle mass in the aged. Therefore, the purposes of this dissertation were to characterize the extrinsic apoptotic pathway within aged skeletal muscles and to test the effectiveness of another cytokine, IL-15, at disrupting this apoptotic pathway. Apoptotic signaling markers involved in the extrinsic pathway, including tumor necrosis factor-alpha (TNF-alpha), TNF receptor (TNFR), fas-associated death domain protein (FADD), TNFR-associated death domain protein (TRADD), caspase-8, caspase-3, BCL-3 interacting domain protein (Bid), and FLICE-inhibiting protein (FLIP), as well as the cytokine interleukin-15 (IL-15), were accessed in skeletal muscles from aged rodents and compared to muscles from young adult rodents. Muscles from aged animals were smaller and the incidence of apoptosis was greater when compared to muscles from young adult rodents. Additionally, aged muscles expressed greater mRNA and protein contents for the apoptotic markers involved in the extrinsic pathway, thereby suggesting the extrinsic pathway is active in skeletal muscles. Furthermore, IL-15 mRNA concentrations were, in general, greater in aged muscles and following periods of muscle unloading. However, over-expression of IL-15 was unable to disrupt this apoptotic pathway in either aged rodents or in myoblast cultures stimulated with TNF-alpha. These data suggest that while the extrinsic apoptotic pathway is active within aged skeletal muscles, and that TNF-alpha is able to promote these apoptotic changes in myoblast cultures, IL-15 is not an effective agent at disrupting this pathway and preserving muscle mass.