We have 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 unexpectedly results in a more severe disease development. Therefore, this project aimed 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. Major findings:
a) We could show that the accumulation of muscle glycogen is also observed in other dysferlin deficient mouse models, indicating the general occurrence of this phenomenon in muscles lacking dysferlin.
b) To assess whether modulation of glycogen metabolism could ameliorate disease progression, we investigated the effects of a 9-month running wheel intervention. This intervention is not intended to induce a consistent lowering of muscle glycogen but rather activate glycogen dynamics in the muscle. Our results revealed that exercise could significantly increase muscle mass in affected dystrophic muscles and substantially improve functional performance.
However, it seems that wheel running exacerbates muscle damage. Therefore, a milder and less muscle-damaging form of exercise (i.e. swimming) might be more beneficial in dysferlinopathies.
c) As exercise-induced glycogen depletion is not impaired in dysferlin-deficient muscles, glycogen accumulation is not likely to be caused by differences in glycogenolysis. Furthermore, we could show that glucose transporters (GLUT1 and GLUT4) are more abundant in muscles lacking dysferlin and that these muscles have a substantially higher glucose uptake. Additionally, the abundance of glycolytic enzymes is considerably lower in dysferlin-deficient muscles,
suggesting that the higher glucose uptake together with lower glycolysis could result in the accumulation of muscle glycogen during disease progression.
Collectively, our data demonstrate that dysferlin deficiency results in an abnormal muscle cell metabolism that could contribute to the disease pathology. This suggests that dysferlin regulates cellular metabolism and more specifically glucose uptake and glycolysis, in addition to its role in controlling membrane repair.