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A novel role of dysferlin in regulating skeletal muscle metabolism contributes to disease pathology in dysferlinopathies

Research Project
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01.04.2021
 - 30.03.2022

Dysferlin is a protein that is intimately involved in the control of membrane repair in damaged cells. Accordingly, mutations of the dysferlin gene cause progressive muscular dystrophies collectively referred to as dysferlinopathies. Unexpectedly though, therapeutic strategies aimed at restoring membrane resealing capabilities fail to prevent the muscular dystrophy in these diseases, indicating other, hitherto unknown molecular functions of dysferlin to contribute to the pathology in dysferlinopathy patients. We have now observed how the pathological progression in a mouse model for Limb-Girdle Muscular Dystrophy type 2B (LGMD2B) is closely linked to altered muscle cell metabolism, most notably an accumulation of glycogen. Moreover, exacerbation of glycogen storage by overexpression of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in these muscles results in a more severe muscle tissue damage, and impaired functionality. Our preliminary data thus indicate that abnormal muscle cell metabolism caused by mutations in the dysferlin gene contribute to the disease pathology, that dysferlinopathies recapitulate some of the aberrant changes observed in glycogen storage diseases such as McArdle's, and finally that dysferlin regulates cellular metabolism in an unknown manner, in addition to its role in controlling membrane repair. We therefore propose a research plan in this grant application that aims at a.) substantiating and validating these findings in different pre-clinical models, b.) obtaining proof-of-concept for therapeutic efficacy of normalization of muscle cell metabolism in LGMD2B, and c.) investigating the molecular underpinnings of the involvement of dysferlin in the regulation of muscle cell metabolism. The expected results will not only shed light on novel aspects of dysferlin function, but should also propose new therapeutic avenues to ameliorate this muscular dystrophies, complementing those targeting membrane repair.

Funding

A novel role of dysferlin in regulating skeletal muscle metabolism contributes to disease pathology in dysferlinopathies

Weitere ausländische Förderagenturen (GrantsTool), 04.2021-03.2022 (12)
PI : Handschin, Christoph.

Members (1)

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Christoph Handschin

Principal Investigator