TRAF 6 Mediates TNF?-induced Skeletal Muscle Sarcopenia In Mice During Aging

During aging,muscle mass and strength and/or function decrease,leading to sarcopenia,associated with low-level chronic inflammation.Patients with a variety of pathologic conditions associated with sarcopenia,including rheumatoid arthritis(RA),have systemically elevated TNFa serum levels,and transgenic mice with TNFa overexpression(TNF-Tg mice,a model of RA)develop sarcopenia between adolescence and adulthood before they age.However,if and how TNF?contributes to the pathogenesis of sarcopenia during the normal aging process and in RA remains largely unknown.We report that TNFa levels are increased in skeletal muscles of aged WT mice,associated with muscle atrophy and decreased numbers of satellite cells and Type ?A myofibers,a phenotype that we also observed in adult TNF-Tg mice.Aged WT mice also have increased numbers of myeloid lineage cells in their skeletal muscles,including macrophages and granulocytes.These cells have increased TNFa expression,which impairs myogenic cell differentiation.Expression levels of TNF receptor-associated factor 6(TRAF6),an E3 ubiquitin ligase,which mediates signaling by some TNF receptor(TNFR)family members,is elevated in skeletal muscles of both aged WT mice and adult TNF-Tg mice.TRAF6 binds to TNFR2 in C2C12 myoblast cells and mediates TNFa-induced muscle atrophy through NF-KB-induced transcription of the muscle-specific E3 ligases,Atrogenl and Murfl,which promote myosin heavy chain degradation.Haplo-deficiency of TRAF6 prevents muscle atrophy and the decrease in numbers of satellite cells,Type ?A myofibers,and myogenic regeneration in TNF-Tg;TRAF6+/-mice.Our findings suggest that pharmacologic inhibition of TRAF6 signaling in skeletal muscles during aging could treat/prevent age-and RA-related sarcopenia by preventing TNF?-induced proteolysis and inhibition of muscle fiber regeneration.