Skeletal Muscle Fatigue and Abnormal Ca2+ Signaling in Friedreich’s Ataxia

Calcium ions (Ca2+) play a central role in skeletal muscle contraction, relaxation, and fatigue. Although muscle weakness and fatigue are widely reported in individuals with Friedreich’s ataxia (FA), there is lack of direct information regarding the mechanisms by which frataxin deficiency leads to muscle dysfunction. Dr Liang generated a pre-clinical mouse model of constitutive, skeletal muscle-specific Fxn deficiency (SkMFxn-KO) that recapitulates key characteristics of muscle dysfunction experienced by individuals with FA. SkMFxn-KO mice exhibit reduced body and muscle mass, decreased muscle force generation, and exercise intolerance. In this proposal, Dr. Liang will take advantage of this model to: 1) characterize muscle fatigue at neuromuscular, whole muscle, and single muscle fiber levels, 2) determine the mechanism by which Fxn deficiency leads to defects in Ca2+ homeostasis in skeletal muscle that results in muscle weakness and fatigue, and 3) evaluate the efficacy mitochondrial-directed antioxidant therapy in counteracting the deficits that result from Fxn deficiency in skeletal muscle. She hypothesizes that Fxn deficiency in skeletal muscle results in increased oxidative stress that alters Ca2+ homeostatic mechanisms in a manner that results in the progressive muscle weakness and fatigue observed in the SkMFxn-KO mice. In addition, she hypothesizes that antioxidant treatment will restore normal Ca2+ homeostasis mechanisms, and thus, ameliorate muscle dysfunction. The outcome of this study will provide new insights into the pathogenic mechanisms and treatment of the debilitating muscle dysfunction experienced by FA patients.