Pathophysiology of Muscle Dysfunction in Friedreich's Ataxia

FRDA is a deadly neurodegenerative disorder that is associated with significant muscle wasting and weakness. However, the reasons for this have not been extensively examined. Given that skeletal muscle plays a critical role in movement and daily activity, there is a pressing need to enhance our understanding of how altered skeletal muscle function contributes to the development and progression of FRDA. A major barrier to achieving this goal has been the lack of an animal model that accurately reflects the clinical features of FRDA in skeletal muscle. To overcome this barrier, Dr. Liang will generate two new pre-clinical mouse models, constitutive and inducible muscle-specific Fxn knockout mice. These mouse models will enable detailed analyses of the role of Fxn in muscle development and function, as well as the acute effect of FXN deficiency on muscle function in adulthood. These mouse models will also be used to identify and test the efficacy of new interventions designed to counteract the deficits that result from Fxn deficiency during development and adulthood. This investigator and her mentors hypothesize that reduced Fxn expression in skeletal muscle results in muscle dysfunction and that restoration of Fxn expression ameliorates muscle dysfunction and prolongs survival. They further hypothesize that Fxn deficiency in skeletal muscle arises from mitochondrial damage due to mitochondrial Ca2+ overload and that muscle function is improved by blocking the activity of mitochondrial permeability transition pore (mPTP) through ablation of cyclophilin D. These hypotheses will be comprehensively evaluated using a multidisciplinary approach that includes muscle physiology, molecular biology, biochemistry, and Ca2+ imaging. The outcome of this study will provide new insights into the pathogenic mechanisms and treatment of the debilitating muscle dysfunction experienced by FRDA patients.