In muscle, mitochondria play a fundamental role in maintaining bioenergetic homeostasis. Mitochondrial dysfunction has been associated with several muscle disorders and mitochondrial function has been shown to be reduced in dysferlinopathy. It is unknown whether this is the result of mitochondrial failure or a metabolically unfavorable, sugar-rich environment. Using a cell culture model of dysferlinopathy, we determined that the absence or the reduction of glucose in the culture media improved mitochondrial function. We observed similar results when the cells were cultured with β-hydroxybutyrate as the main energy substrate.
These experiments demonstrate that mitochondria are not dysfunctional in cells lacking dysferlin, but they turn off. To determine whether the activation of mitochondria by changes in the energetic substrate impact in the survival of the cells after a mechanical stress, we challenged cells cultured in different media. Interestingly, only the dysferlinopathy cells cultured in a high glucose media had a significant death rate, while cells cultured in β-hydroxybutyrate or in galactose (no glucose) survived at a similar rate to cells with dysferlin. We concluded that the activation of mitochondria, achieved by a change in food source, helps dysferlin-deficient cells cope with stress.
We also investigated whether a reduction in dietary carbohydrate improves muscle perform in a mouse model of dysferlinopathy (Bla/J). We fed pre-symptomatic mice either a ketogenic diet (low carbohydrate-high fat), an isocaloric control diet (high carbohydrate-low fat), or regular chow for three months. We then assessed muscle strength using the grip test, motor coordination using a rotarod, and endurance on a treadmill. We found that the mice fed with a ketogenic diet maintained or improved their strength or motor coordination performance to the level shown by the wild type mice. This correlates with an increase in the mitochondrial mass of different muscles, as determine by an increase of the mitochondrial marker VDAC by Western blot. Overall, we concluded that removing carbohydrate as the main energetic substrate, and replacing it with ketone bodies, improves mitochondrial function and therefore resistance to stress and muscle performance.