IRS1 and cardiomyopathy: To resolve this apparent paradox between the poor reputation of mTORC1 in the lipid overloaded insulin-resistant heart and the potential beneficial use of mTORC1 activation as a therapeutic strategy to cure lipid-induced cardiomyopathy, we speculate the following: While under basal conditions, mTORC1 is localized at the endosomal membranes (Figure 2A), and it has to migrate into the cytoplasm to gain access to IRS1 for performing the inhibitory Ser-phosphorylation [43].