Cachexia is a highly debilitating multifactorial syndrome affecting more than 50% of patients with advanced cancer, characterized by severe muscle wasting leading to pronounced weight loss, impaired quality of life, reduced response to anti-cancer therapy, and premature death. Inflammatory cytokines, such as TNFα are the main atrophy-inducing factors in cachexia causing excess catabolism of myofibrillary proteins through activation of the ubiquitin-proteasome systems (UPS)1 . An unexpected connection between the muscle-specific transcription factor, myogenin, and the induction of atrogenes expression in different atrophying conditions (including TNFα-induced atrophy) has been reported2,3. However, the receptor able to upregulate myogenin expression in atrophying conditions has not been identified yet. We demonstrated that an appropriate recruitment of RAGE (receptor for advanced glycation-end products) by its ligands, S100B and HMGB1, concurs to skeletal muscle development and restoration of muscle homeostasis in physiological conditions and upon acute muscle injury4 . Here, we investigated whether RAGE might up-regulate the expression of myogenin via p38 MAPK pathway in atrophying conditions, as in the case of myoblasts, and lead to activation of the catabolic program. We found that: i) Lewis lung carcinoma (LLC)-bearing mice re-express RAGE in myofibers and myogenin in myonuclei; ii) muscles of LLC-bearing RAGE-null (Ager‒/‒) mice show reduced loss of mass and reduced Fbxo32 (atrogin1), Trim63 (MuRF1) and myogenin expression compared with LLC-bearing WT mice; iii) the upregulation of Ager in atrophying C2C12 myotubes precedes the increase in Myog (myogenin), Fbxo32 and Trim63 levels; iv) RAGE signaling is involved in the mechanism through which TNFα induces atrophy in vitro (i.e., upregulation of myogenin via activation of the catabolic kinase, p38 MAPK); and v) high doses of S100B, as found in the serum of cachectic mice, induce up-regulation of RAGE and myogenin expression with concomitant activation of p38 MAPK and induction of the UPS in myotubes and in muscle tissue. Thus, increased expression/activity of the RAGE/ p38 MAPK/myogenin axis in muscle tissue appears to concur to cancer cachexia. 1. Porporato P.E., 2016, Oncogenesis 22(5): e200; 2. Moresi V. et al., 2010, Cell 143: 35-34; 3. Minetti G.C. et al., 2011, Sci Sign 4: ra80; 4. Riuzzi F. et al., 2012, J Cell Sci 125:1440-1454.
Involvement of a RAGE/p38MAPK/myogenin axis in cancer cachexia.
Chiappalupi S.;Vukasinovic A.;Salvadori L.;Sorci G;Riuzzi F.
;and Donato R
2018
Abstract
Cachexia is a highly debilitating multifactorial syndrome affecting more than 50% of patients with advanced cancer, characterized by severe muscle wasting leading to pronounced weight loss, impaired quality of life, reduced response to anti-cancer therapy, and premature death. Inflammatory cytokines, such as TNFα are the main atrophy-inducing factors in cachexia causing excess catabolism of myofibrillary proteins through activation of the ubiquitin-proteasome systems (UPS)1 . An unexpected connection between the muscle-specific transcription factor, myogenin, and the induction of atrogenes expression in different atrophying conditions (including TNFα-induced atrophy) has been reported2,3. However, the receptor able to upregulate myogenin expression in atrophying conditions has not been identified yet. We demonstrated that an appropriate recruitment of RAGE (receptor for advanced glycation-end products) by its ligands, S100B and HMGB1, concurs to skeletal muscle development and restoration of muscle homeostasis in physiological conditions and upon acute muscle injury4 . Here, we investigated whether RAGE might up-regulate the expression of myogenin via p38 MAPK pathway in atrophying conditions, as in the case of myoblasts, and lead to activation of the catabolic program. We found that: i) Lewis lung carcinoma (LLC)-bearing mice re-express RAGE in myofibers and myogenin in myonuclei; ii) muscles of LLC-bearing RAGE-null (Ager‒/‒) mice show reduced loss of mass and reduced Fbxo32 (atrogin1), Trim63 (MuRF1) and myogenin expression compared with LLC-bearing WT mice; iii) the upregulation of Ager in atrophying C2C12 myotubes precedes the increase in Myog (myogenin), Fbxo32 and Trim63 levels; iv) RAGE signaling is involved in the mechanism through which TNFα induces atrophy in vitro (i.e., upregulation of myogenin via activation of the catabolic kinase, p38 MAPK); and v) high doses of S100B, as found in the serum of cachectic mice, induce up-regulation of RAGE and myogenin expression with concomitant activation of p38 MAPK and induction of the UPS in myotubes and in muscle tissue. Thus, increased expression/activity of the RAGE/ p38 MAPK/myogenin axis in muscle tissue appears to concur to cancer cachexia. 1. Porporato P.E., 2016, Oncogenesis 22(5): e200; 2. Moresi V. et al., 2010, Cell 143: 35-34; 3. Minetti G.C. et al., 2011, Sci Sign 4: ra80; 4. Riuzzi F. et al., 2012, J Cell Sci 125:1440-1454.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
