Mechanistic Basis of Skeletal Muscle Wasting Diseases

Abstract

Skeletal muscle is the largest tissue in the human body by biomass and it is essential for life. Impaired skeletal muscle function can negatively impact one's quality of life but in the case of diseases like cancer cachexia, it can directly contribute to death of patients. Skeletal muscle wasting is a key feature of many monogenic muscle diseases such as Duchenne muscular dystrophy (DMD) and Emery-Dreifuss muscular dystrophy (EDMD) but also more complex conditions such as cancer cachexia, starvation, and various neuromuscular diseases. Throughout this thesis, I focus on two muscle wasting diseases, cancer cachexia and EDMD. While these diseases have been studied for decades, with the disease-causing genes being identified for EDMD, the mechanistic basis has not been elucidated for either disease. Here we propose that downregulation of the nuclear envelope protein, Net39, contributes to EDMD pathogenesis. Adult deletion of Net39 in mice recapitulates many of the key features of EDMD, including nuclear envelope deformations, dysregulated gene expression, altered metabolism, and muscle wasting. Mechanistically, Net39 protects myonuclear envelopes from mechanical stretch and nuclear envelopes deficient of Net39 are structurally compromised, leading to DNA damage. Cancer cachexia on the other hand, is a highly prevalent and systemic wasting condition characterized by skeletal muscle wasting. We profiled the molecular changes at play in mouse and human cachexic muscle at single nuclear resolution, identifying the conserved activation of a denervation gene program. Mechanistically, we discovered that myogenin regulates myostatin during cancer cachexia and the inhibition of myostatin via AAV-Follistatin gene therapy rescues cancer cachexia and prolongs survival in preclinical models of cancer. Overall, our findings here highlight the importance of Net39 to EDMD pathogenesis and the myogenin-myostatin axis to cancer cachexia-induced muscle atrophy