TNF Receptor-Associated Factor 6 Mediates TNFα-Induced Skeletal Muscle Atrophy in Mice During Aging

Abstract

During aging, muscle mass decreases, leading to sarcopenia, associated with low-level chronic inflammation (inflammaging), which induces sarcopenia by promoting proteolysis of muscle fibers and inhibiting their regeneration. Patients with a variety of pathologic conditions associated with sarcopenia, including rheumatoid arthritis (RA), have systemically elevated TNFα serum levels, and transgenic mice with TNFα overexpression (TNF-Tg mice, a model of RA) develop sarcopenia between adolescence and adulthood before they age. However, if and how TNFα contributes to the pathogenesis of sarcopenia during the normal aging process and in RA remains largely unknown. We report that TNFα levels are increased in skeletal muscles of aged WT mice, associated with muscle atrophy and decreased numbers of satellite cells and Type IIA 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 TNFα 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, are elevated in skeletal muscles of both aged WT mice and adult TNF-Tg mice. TRAF6 binds to TNFR2 in C2C12 myoblasts and mediates TNFα-induced muscle atrophy through NF-κB-induced transcription of the muscle-specific E3 ligases, Atrogen1 and Murf1, which promote myosin heavy-chain degradation. Haplo-deficiency of TRAF6 prevents muscle atrophy and the decrease in numbers of satellite cells, Type IIA myofibers, and myogenic regeneration in TRAF6 +/− ;TNF-Tg 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 TNFα-induced proteolysis and inhibition of muscle fiber regeneration.

Inflammation and metabolism: the role of adiposity in sarcopenic obesity

“…Switching the focus to MPB upon local inflammatory stimuli, by binding to TNFR1, the role of TNFα-induced skeletal muscle loss in ageing mice was pinpointed to the NF-κB-mediated activation of E3 ligases (MAFbx and MuRF-1) and p38MAPK. By virtue of ubiquitination of MyHC proteins and induced malfunction of skeletal muscle satellite cells, NF-κB promoted protein degradation and impaired regeneration (25,129) (previous murine data supports these findings (124)(125)(126)130) ). TNFα acts in a positive feedback loop to increase the transcription of additional TNFα, as well as IL-1β and IL-6, which feed into chronic inflammation and reactive oxygen species production, leading to NF-κB-mediated ubiquitination and protein degradation (25) .…”

Ubiquitin Ligases at the Heart of Skeletal Muscle Atrophy Control

“…TRAF6 is a RING-type Ub ligase that plays an important role during skeletal muscle atrophy. TRAF6 expression is enhanced during starvation or within aged-induced muscle atrophy [ 179 , 196 , 197 ]. Traf6 -KO mice are resistant to skeletal muscle loss (rescue of myofibril degradation, preservation of myofiber size and strength) induced by denervation, cancer cachexia, starvation or Dex and a concomitant suppression of the expression of key regulators of muscle atrophy was observed, including MAFBx/Atrogin-1, MuRF1/TRIM63, p62, Lc3b, Beclin1, Atg12, and Fn14 [ 179 , 180 , 196 , 197 , 198 ].…”

“…TRAF6 expression is enhanced during starvation or within aged-induced muscle atrophy [ 179 , 196 , 197 ]. Traf6 -KO mice are resistant to skeletal muscle loss (rescue of myofibril degradation, preservation of myofiber size and strength) induced by denervation, cancer cachexia, starvation or Dex and a concomitant suppression of the expression of key regulators of muscle atrophy was observed, including MAFBx/Atrogin-1, MuRF1/TRIM63, p62, Lc3b, Beclin1, Atg12, and Fn14 [ 179 , 180 , 196 , 197 , 198 ]. Moreover, inhibition of Traf6 expression through miR-351 administration in C2C12 myotubes or in denervated mice attenuated Dex-induced muscle atrophy and concomitantly decreased the expression of MAFBx/Atrogin-1 and MuRF1/Trim63 [ 199 , 200 ].…”

Docosahexaenoic Acid, a Potential Treatment for Sarcopenia, Modulates the Ubiquitin–Proteasome and the Autophagy–Lysosome Systems

“…Although the contributions of atrogin-1, MuRF1, and other E3 ligases, such as TNF receptor-associated factor 6 (TRAF6) [94], the C-terminus of Hsc70 interacting protein (CHIP/STUB1), and E6-associated protein (E6AP) [72], to muscle atrophy have been widely studied, little is known about how 26S proteasome affects muscle protein degradation during aging. Proteasomes are generally regarded as highly abundant and stable [95,96].…”