The Transcriptional Coregulators TIF2 and SRC-1 Regulate Energy Homeostasis by Modulating Mitochondrial Respiration in Skeletal Muscles

SummaryThe two p160 transcriptional coregulator family members SRC-1 and TIF2 have important metabolic functions in white and brown adipose tissues as well as in the liver. To analyze TIF2 cell-autonomous functions in skeletal muscles, we generated TIF2(i)skm−/− mice in which TIF2 was selectively ablated in skeletal muscle myofibers at adulthood. We found that increased mitochondrial uncoupling in skeletal muscle myocytes protected these mice from decreased muscle oxidative capacities induced by sedentariness, delayed the development of type 2 diabetes, and attenuated high-caloric-diet-induced obesity. Moreover, our results demonstrate that SRC-1 and TIF2 can modulate the expression of the uncoupling protein 3 (UCP3) in an antagonistic manner and that enhanced SRC-1 levels in TIF2-deficient myofibers are critically involved in the metabolic changes of TIF2(i)skm−/− mice. Thus, modulation of the expression and/or activity of these coregulators represents an attractive way to prevent or treat metabolic disorders.

Graphical AbstractFigure optionsDownload high-quality image (206 K)Download as PowerPoint slideHighlights
► Skeletal muscle myocyte TIF2 controls whole-body energy balance
► TIF2 optimizes mitochondrial coupling in skeletal muscles
► Mitochondrial uncoupling protects from adverse effects of sedentariness
► TIF2 is a potential drug target to prevent metabolic disorders