Ketogenic diet induces skeletal muscle atrophy via reducing muscle protein synthesis and possibly activating proteolysis in mice

Ketogenic diets (KD) that are very high in fat and low in carbohydrates are thought to simulate the metabolic effects of starvation. We fed mice with a KD for seven days to assess the underlying mechanisms of muscle wasting induced by chronic starvation. This diet decreased the weight of the gastrocnemius (Ga), tibialis anterior (TA) and soleus (Sol) muscles by 23%, 11% and 16%, respectively. The size of Ga, TA, Sol muscle fibers and the grip strength of four limbs also significantly declined by 20%, 28%, 16% and 22%, respectively. The muscle atrophy-related genes Mafbx, Murf1, Foxo3, Lc3b and Klf15 were upregulated in the skeletal muscles of mice fed with the KD. In accordance with the reduced expression of anabolic genes such as Igf1, surface sensing of translation (SUnSET) analyses of fast-twitch Ga, TA and Sol muscles revealed that the KD suppressed muscle protein synthesis. The mRNA expression of oxidative stress-responsive genes such as Sod1 was significantly increased in all muscles examined. In addition to hypercorticosteronemia, hypoinsulinemia and reduced IGF-1, oxidative stress might also be involved in KD-induced muscle atrophy. Feeding mice with a KD is a novel experimental animal model of muscle-wasting induced by chronic starvation.