Autophagy activation via BAG3 gene therapy improves phenotype in a mouse model of LGMD1A.

Myofibrillar myopathies (MFMs) are a group of protein aggregate diseases characterized by abnormal protein aggregations and myofibrillar disintegration. Myotilinopathy, also named MFM3 or limb-girdle muscular dystrophy type 1A (LGMD1A), is caused by myotilin mutations. Myotilin is degraded by the ubiquitin-proteasome system; however, when this pathway is overloaded under pathophysiological conditions, the protein quality control system leans on the autophagy-lysosome pathway (ALP) to mediate degradation of aggregates. BCL2-associated athanogene 3 (BAG3) protein facilitates aggresome formation and initiates ALP. In this study, we assessed our strategy of reducing the aggregate burden in muscle by overexpressing human BAG3 in TgT57I mice, a model for LGMD1A. Overexpression was achieved by systemic delivery of AAVrh74.tMCK.hBAG3, and outcome measures included functional, histological, and molecular studies. The hBAG3-treated cohort demonstrated increased rotarod duration, treadmill running distance, grip strength, and maximum tetanic response compared to the untreated cohort. Myotilin aggregate burden was significantly decreased, and autophagy levels were normalized in the treated group. As an adaptive response, hBAG3 normalized the endogenous Bag1/Bag3 ratio to that of 3-month-old TgT57I mice. This study provides evidence that our strategy of reducing the aggregate burden in muscle by overexpressing BAG3 may be used as a treatment for protein aggregate myopathies.