Background: It’s known that Mineralocorticoid Receptor (MR) activation affects adipocytes differentiation and function and we showed that MR antagonism is able to improve insulin-stimulated glucose uptake in a mouse model of diet-induced obesity and insulin resistance. Adipose tissue secretome shows a paracrine effect on vascular system and cardiac function, as well as on skeletal muscle metabolism. Interestingly, MR blockade is able to affect skeletal muscle metabolism, improving insulin signaling. In addition, renin-angiotensin-aldosterone system (RAAS) activation, through MR-dependent mechanisms, leads to skeletal muscle athrophy in mice. Purpose: Our aim is to evaluate a possible involvement of MR activation in regulat- ing skeletal muscle differentiation and function in vitro and in vivo. Methods: We investigated the involevement of MR in regulating murine skeletal muscle cells (C2C12) differentiation and we started to characterize the impact of adipose MR activation on skeletal muscle metabolic profile and development in a novel adipose-specific MR knockout (MRKO) mouse model. Results: We first characterized the ontogenensis of MR in a murine myoblast cell line (C2C12) by RT-PCR and western blot analyses in order to evaluate the expression of MR during myotubes differentiation in vitro. We observed an increase in MR protein expression in skeletal myotubes during differentiation (96h). To evaluate the effects of MR activity on C2C12 cells, we treated C2C12 myoblasts, after differentiation stimulus, with aldosterone (Aldo, 10-8 mol/L) for 6h and 24h and we observed that Aldo significantly reduced Heavy Chain Myosin (MHC) mRNA levels, suggesting that MR activity represses muscle cell differentiation. Such effect was also MR dependent, given that Spiro was able to revert such effect. We also analyzed skeletal muscle insulin sensitivity in vivo in MRKO mice eval- uating soleus muscle insulin receptor substarte-1, tyrosinephosphorylated IRS-1, GLUT4 levels mRNA expression and Akt phosphorylation. Interestingly, we observed improved soleus muscle insulin signaling parameters and systemic insulin sensitivity in MRKO mice compared to controls. Further studies are necessary to explore the effect of MR activation on skeletal muscle development in vivo. Conclusions: These data reveal a potential role of MR in modulating skeletal mus- cle differentiation and insulin sensitivity, which suggest a potential application of MR antagonists to improve skeletal muscle function.
Mineralocorticoid receptor activation affects skeletal muscle development and metabolism
Ferraro E
2016-01-01
Abstract
Background: It’s known that Mineralocorticoid Receptor (MR) activation affects adipocytes differentiation and function and we showed that MR antagonism is able to improve insulin-stimulated glucose uptake in a mouse model of diet-induced obesity and insulin resistance. Adipose tissue secretome shows a paracrine effect on vascular system and cardiac function, as well as on skeletal muscle metabolism. Interestingly, MR blockade is able to affect skeletal muscle metabolism, improving insulin signaling. In addition, renin-angiotensin-aldosterone system (RAAS) activation, through MR-dependent mechanisms, leads to skeletal muscle athrophy in mice. Purpose: Our aim is to evaluate a possible involvement of MR activation in regulat- ing skeletal muscle differentiation and function in vitro and in vivo. Methods: We investigated the involevement of MR in regulating murine skeletal muscle cells (C2C12) differentiation and we started to characterize the impact of adipose MR activation on skeletal muscle metabolic profile and development in a novel adipose-specific MR knockout (MRKO) mouse model. Results: We first characterized the ontogenensis of MR in a murine myoblast cell line (C2C12) by RT-PCR and western blot analyses in order to evaluate the expression of MR during myotubes differentiation in vitro. We observed an increase in MR protein expression in skeletal myotubes during differentiation (96h). To evaluate the effects of MR activity on C2C12 cells, we treated C2C12 myoblasts, after differentiation stimulus, with aldosterone (Aldo, 10-8 mol/L) for 6h and 24h and we observed that Aldo significantly reduced Heavy Chain Myosin (MHC) mRNA levels, suggesting that MR activity represses muscle cell differentiation. Such effect was also MR dependent, given that Spiro was able to revert such effect. We also analyzed skeletal muscle insulin sensitivity in vivo in MRKO mice eval- uating soleus muscle insulin receptor substarte-1, tyrosinephosphorylated IRS-1, GLUT4 levels mRNA expression and Akt phosphorylation. Interestingly, we observed improved soleus muscle insulin signaling parameters and systemic insulin sensitivity in MRKO mice compared to controls. Further studies are necessary to explore the effect of MR activation on skeletal muscle development in vivo. Conclusions: These data reveal a potential role of MR in modulating skeletal mus- cle differentiation and insulin sensitivity, which suggest a potential application of MR antagonists to improve skeletal muscle function.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
