Research Paper Volume 15, Issue 6 pp 1808—1832

Figure 7. Summary schematic of MET+LEU effects during SD in muscle cells. Following atrophic stimuli (serum deprivation (SD)), acutely (within 4 hours) AMPKα signaling increased while mTORC1 signaling decreased. With chronic (4 days) serum deprivation, cellular senescence and inflammation related to the senescence-associated secretory phenotype (SASP) are increased. These contribute to disrupted proteostasis (decreased protein synthesis and increased protein breakdown) that eventually caused myotube atrophy. MET+LEU appears to inhibit SD-induced cellular senescence and inflammatory-related SASP which may have caused the prevention in proteasome activity observed with MET+LEU, independent of AMPKα and mTORC1 signaling. MET+LEU was also effective in preventing myotube atrophy following other modes of atrophic stimuli (TNF-α- and lipid-induced) while also reducing atrophy ex vivo in aged myofibers and preventing a decline in aged human primary myotube myonuclei fusion.