Exercise‐based interventions in dysferlinopathies

Prof. Christoph Handschin, Biozentrum, University of Basel


Abstract (Lay summary see below)

Dysferlin is a protein that is involved in different aspects of muscle cell biology, with a prominent role in damageinduced membrane repair. Mutations in the dysferlin gene result in muscular dystrophies collectively referred to as dysferlinopathies. To date, efficient interventions for the prevention and treatment of these pathologies remain elusive. Based on the known functions of dysferlin, exercise‐based interventions could be expected to alleviate many of the symptoms. However, since some specific exercise paradigms have been associated with a detrimental outcome, at least in mouse models for this disease, the adaptations linked to exercise might have to be achieved by alternative means to design safe therapeutic approaches. Our project aims at a better understanding of the function of dysferlin, the mechanisms that underlie the disease pathology and ultimately, the use of genetic and pharmacological interventions that elicit potential beneficial effects. These interventions are centered on the peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α), a key regulatory nexus of endurance exercise adaptation of skeletal muscle. A comprehensive analysis using in silico, in vitro and in vivo techniques will help to identify novel modalities to enhance membrane resealing, improve fiber repair, boost muscle regeneration and eventually enhance muscle function in dysferlinopathies. 

Lay summary

Prof. Christoph Handschin untersucht den Einfluss des Proteins PGC-1alpha auf die Membranintegrität, Muskelschäden und –funktion in Dysferlinopathien. In diesen Muskelkrankheiten ist die Reparatur der Membran gestört und dadurch Muskelfasern anfälliger auf mechanischen Stress. PGC-1alpha reguliert verschiedene Anpassungsvorgänge im Muskel, die durch Ausdauertraining ausgelöst werden, damit auch solche, die den Muskel resistenter gegen Beschädigungen machen, die Regeneration verbessern, und einen positiven Einfluss auf den Muskelmetabolismus hervorrufen. Ziel des Projekts ist es zu studieren, ob diese Eigenschaften einen therapeutischen Effekt in einem Mausmodell für Dysferlinopathien auslösen, ähnlich wie früher schon in anderen Muskelkrankheiten beobachtet wurde.