Energy substrate levels and metabolic changes in skeletal muscle underlie increased activity and improved exercise performance in liver fatty acid‐binding protein null mice

Abstract

Liver fatty acid‐binding protein (LFABP, FABP1) binds long chain fatty acids with high affinity, and is abundantly expressed in the liver and small intestine. Although LFABP is thought to function in intracellular lipid trafficking, studies of LFABP null (LFABP−/−) mice have also demonstrated a role in regulation of systemic energy homeostasis. We and others have reported that LFABP−/− mice become more obese than wild‐type (WT) mice upon high fat feeding. Despite increased body weight and fat mass, however, and in marked contrast to the drastic decrease in exercise capacity in high fat‐fed WT mice, LFABP−/− mice were able to maintain their endurance exercise performance, showing an approximate doubling of running distance compared with the WT mice. Therefore, to understand this surprising exercise phenotype, in the present studies we focused on the metabolic alterations in the skeletal muscle secondary to LFABP ablation. The results indicate significantly increased triglyceride (TG) content and glycogen content in the skeletal muscle of LFABP−/− mice. In addition, higher mitochondrial enzyme activities, in both the tricarboxylic acid (TCA) cycle and the electron transport chain, suggest that LFABP−/− muscle has greater energy substrate availability and greater capacity for substrate oxidation compared with WT muscle. Moreover, consistent with the findings that their muscle Pgc1α and Pparα mRNA levels were upregulated, LFABP−/−mice had an increased fatty acid oxidation rate in the skeletal muscle compared with WT mice. Interestingly, however, substrate utilization during exercise showed no differences between LFABP−/− and WT mice, as examined by respiratory exchange ratio, exercise‐dependent decreases in muscle TG and glycogen stores, and 5′AMP‐activated protein kinase activation levels. Thus, the LFABP−/− and WT mice appear to have similar energy production during exercise, indicating that the markedly improved exercise capacity in the LFABP−/− mice is related to their higher muscle substrate levels prior to exercise. Overall, the results show that although it is not expressed in muscle, LFABP ablation in the liver and intestine is associated with alterations in skeletal muscle energy metabolism and energy substrate levels. These changes may be due, in part, to liver‐and/or intestine‐derived mediators that contribute to the greater TG and glycogen availability and increased mitochondrial function, thereby preventing the high fat feeding‐induced decrease in exercise capacity.Support or Funding InformationThis work was supported by National Institutes of Health Grant DK‐38389 from NIDDK, and by funds from the New Jersey Agricultural Experiment Station (to J. S.).