Female Mice Are Protected from Metabolic Decline Associated with Lack of Skeletal Muscle HuR

SIMPLE SUMMARY: Metabolic flexibility describes the ability to adapt to utilization of metabolic fuels such as carbohydrates, lipids, and proteins as they become available. The RNA binding protein HuR controls this flexibility in mouse and human skeletal muscle, but the molecular mechanisms governing this process remain poorly characterized. Additionally, studies from mice indicate that HuR control of metabolic flexibility may be more essential for males than females. This is because males lacking HuR in skeletal muscle develop hallmarks of insulin sensitivity, while females have not been shown to do so. Here we examine this sexual dimorphism in mice lacking HuR in skeletal muscle. Our results reveal that lack of HuR in skeletal muscle drives increased adiposity regardless of sex, but that this increase in adiposity drives the development of insulin resistance in male animals only. Additionally, relative to male mice, the detrimental metabolic phenotype associated with HuR inhibition in skeletal muscle can be corrected by feeding of a diet heavily composed of either lipids or carbohydrates. ABSTRACT: Male mice lacking HuR in skeletal muscle (HuR(m−/−)) have been shown to have decreased gastrocnemius lipid oxidation and increased adiposity and insulin resistance. The same consequences have not been documented in female HuR(m−/−) mice. Here we examine this sexually dimorphic phenotype. HuR(m−/−) mice have an increased fat mass to lean mass ratio (FM/LM) relative to controls where food intake is similar. Increased body weight for male mice correlates with increased blood glucose during glucose tolerance tests (GTT), suggesting increased fat mass in male HuR(m−/−) mice as a driver of decreased glucose clearance. However, HuR(m−/−) female mice show decreased blood glucose levels during GTT relative to controls. HuR(m−/−) mice display decreased palmitate oxidation in skeletal muscle relative to controls. This difference is more robust for male HuR(m−/−) mice and more exaggerated for both sexes at high dietary fat. A high-fat diet stimulates expression of Pgc1α in HuR(m−/−) male skeletal muscle, but not in females. However, the lipid oxidation Pparα pathway remains decreased in HuR(m−/−) male mice relative to controls regardless of diet. This pathway is only decreased in female HuR(m−/−) mice fed high fat diet. A decreased capacity for lipid oxidation in skeletal muscle in the absence of HuR may thus be linked to decreased glucose clearance in male but not female mice.