Cardiolipin metabolism regulates myoD1 expression and muscle development
Linh Vo, Nevton T. Da Rosa J., Michael W. Schmidtke, and Miriam L. Greenberg Department of Biological Sciences, Wayne State University, Detroit, Michigan, USA
Barth syndrome (BTHS) is a life-threatening genetic disorder caused by mutations in tafazzin (TAZ), a protein that remodels newly synthesized cardiolipin (CL) into more unsaturated CL species. BTHS results in a broad range of disorders, including cardiomyopathy, skeletal myopathy, and neutropenia. A major obstacle to developing effective BTHS treatments is that the mechanisms linking CL deficiency with BTHS pathology, especially cardio- and skeletal myopathy, are poorly understood. Our previous study shows that differentiation of myoblasts into myotubes is significantly reduced in TAZ-knockout (TAZ-KO) mouse C2C12 myoblast cells. To gain insight into the mechanisms underlying this defect, we carried out a transcriptomic analysis comparing the expression profile of undifferentiated TAZ-KO cells with that of wild type. Our data revealed that one of the most highly repressed pathways in TAZ-KO cells is cardiac and skeletal muscle growth and development. Within this pathway, we discovered that myoblast determination protein 1 (MyoD1), a master transcription factor regulating muscle differentiation, is highly down-regulated in both TAZ-KO cells and TAZ-KO mouse hearts. Our data further show that the MyoD1 negative regulator homeobox protein Mohawk (MKX) is significantly up-regulated in TAZ-KO cells. Because Wnt signaling has been shown to regulate MKX expression, we speculate that aberrant Wnt signaling may underlie MyoD1 repression and the associated differentiation defects observed in TAZ-KO cells. Our study identifies for the first time that MyoD1 is repressed in TAZ-KO cells and suggests a novel mechanism linking TAZ deficiency to defective myogenesis. These findings identify a new regulatory pathway that links CL with muscle development and may inform potential new treatments for alleviating skeletal myopathy in BTHS patients.
