P.63 - TIEG1 is a novel regulator of muscle mitochondrial biogenesis

Abstract

TGFβ inducible early gene-1 (TIEG1) is a member of KLF family that regulates gene expression in multiple cell and tissue types. Our first investigation in fast (EDL) and slow (soleus) twitch skeletal muscles provided new insights about the role of TIEG1 in the functional and structural properties. TIEG1 Knockout (KO) muscle showed a hyperplasia and hypertrophy of all fiber types along with an increase in glycolytic fibers and a decrease in oxidative fibers. Then we performed transmission electron microscopy (TEM), histochemical (SDH: succinate dehydrogenase, COX: cytochrome c oxidase, etc) and mitochondrial function assays on soleus and EDL of WT and TIEG1 KO mice. In mutant tissues, TEM revealed muscle disorganization, shorter sarcomeres, disappearance of I bands, decreased mitochondria mass and changes in mitochondrial shape. Histochemical analysis demonstrated a total absence of SDH staining and a decrease of COX in TIEG1 KO soleus muscle. These phenomena were also observed, but to a lesser degree, in TIEG1 KO EDL muscle likely due to its glycolytic profile. Mitochondrial biogenesis downregulation in mutants was confirmed in soleus muscle by decrease in the complex I, COX and citrate synthase activities while only complex I (the main controller step of the electron flux through electron-transport chain) was inhibited in TIEG1 KO EDL muscle. These data demonstrate that TIEG1 deficiency alters mitochondrial properties in a muscle-type specific manner. Furthermore, when TIEG1 KO mice were subjected to treadmill exercise, they tired more quickly than WT controls. These characteristics resemble human diseases associated with exercise intolerance. Therefore, TIEG1 KO mice are a useful model system to study the cellular and molecular mechanisms controlling mitochondrial function and muscle metabolism which pertains to multiple muscle related diseases and disorders.