Ketogenic diets consisting of a high lipid and protein content and thus essentially lacking carbohydrates have been developed as a treatment for children with refractory epilepsy in the early 1920s, and it is still today an established treatment for pediatric epilepsy. Moreover, ketogenic diets have also been suggested to have therapeutic potential in diseases of different etiological origin, such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, mitochondrial myopathies, obesity, type 2 diabetes, cardiovascular disease and cancer. Furthermore, the Atkins diet, a variation of a ketogenic diet at least in the induction phase, has gained enormous traction for body weight reduction. One important hallmark of a ketogenic diet is increased mitochondrial function in target organs, and ketogenic diets have shown to be effective in ameliorating several diseases with a mitochondrial etiology. Surprisingly, despite its wide application, relatively little is known regarding the mechanistic aspects of a ketogenic diet, and it is in many cases unclear how its therapeutic effects are mediated. Many studies in this area focus on the production of ketone bodies in the liver, as well as the metabolism of ketone bodies in the brain, specifically in regard to its anticonvulsant effects. In contrast, very few studies focus on the effects of a ketogenic diet on skeletal muscle, which is one of the major ketone body consumers during a state of ketosis. Importantly, skeletal muscle responds differently to a chronic state of ketosis compared to liver. It has been shown in mice that a prolonged ketogenic diet leads to hepatic steatosis and insulin resistance while insulin sensitivity in muscle in maintained, accompanied by an increase in peripheral glucose disposal. Furthermore, ketogenic diets have also been shown to ameliorate pathologies in a mouse model of mitochondrial myopathy, and these findings warrant a closer look at the effects of a ketogenic diet on muscle function and metabolism.

In our present project, we aim at investigating the short- and long-term consequences of a ketogenic diet on skeletal muscle metabolism and function, as well as how ketone body uptake and utilization in skeletal muscle is regulated during a state of ketosis. Preliminary data from our lab define a novel role for peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) as a regulator of skeletal muscle ketone body utilization, and we hypothesize that ablation of PGC-1α specifically in muscle would affect the systemic response to a ketogenic diet. Furthermore, due to the known functions of PGC-1α as a master mitochondrial regulator, we also hypothesize that the absence of PGC-1α would lead to a dysregulation of mitochondrial and metabolic adaptations in skeletal muscle during a ketogenic diet. Through the use of cell culture models, we also aim to delineate the regulation of genes involved in ketone body metabolism imparted by PGC-1α, as well as its potential binding partners in this regulation. This data will further the understanding of how skeletal muscle responds to a ketogenic diet, which will prove useful for both the future application of ketogenic diets in the treatment of muscle related disorders, but also for the general understanding of the processes involved in ketone body metabolism.