Metabolic and Molecular Framework for the Enhancement of Endurance by Intermittent Fasting

Evolutionary considerations suggest that the body has been optimized to perform at a high level in the fasted state when fatty acids and their ketone metabolites are a major fuel source for muscle cells. Because fasting is the most potent physiological stimulus for ketosis, we designed a study to determine the impact of intermittent fasting during endurance training on performance, and to elucidate the underlying cellular and molecular mechanisms. Male mice were randomly assigned to either ad libitum feeding or alternate-day fasting (AF) groups, and half of the mice in each diet group were trained daily on a treadmill for 1 month (45 minutes of running with increasing speed or incline each week). A run to exhaustion endurance test performed at the end of the training period revealed superior performance in the mice maintained on AF during training compared to mice fed ad libitum during training. VO2max was increased similarly by treadmill training in mice on AF or ad libitum diets, whereas respiratory exchange ratio (RER) was reduced in AF mice on fasting days and during running. Analyses of gene expression in liver and soleus tissues, and metabolomics analysis of blood suggest that the metabolic switch invoked by AF and potentiated by exercise strongly modulate molecular pathways involved in mitochondrial biogenesis, metabolism and cellular plasticity. Our findings demonstrate intermittent fasting engages metabolic and cellular signaling pathways that result in increased metabolic efficiency and endurance capacity. Six month-old male C57BL/6J mice were randomly assigned to one of four groups: a sedentary control group fed ad libitum (CTRL); a sedentary group on alternate-day fasting (AF); a group with daily treadmill running exercise fed ad libitum (EX); and a group that ran every day on a treadmill while on AF (EXAF) during a 4-week study period.