Myostatin Deletion Improves Insulin Resistance and Vascular Function in Obese Mice

Insulin resistance in tissues such as muscle and fat is an underlying cause of obesity‐induced vascular dysfunction. Myostatin, secreted by skeletal muscle, has been associated with muscle metabolism and lowering myostatin may improve insulin sensitivity. Hypothesis Increasing muscle mass via myostatin deletion in obesity improves whole‐body metabolism and vascular function. A dual knockout (KO) approach was used including dual heterozygous lean mice, lean myostatin KO, db/db and db/db mice with and without myostatin KO. Myostatin KO increased gastrocnemius and gluteal muscle mass (37–52% in lean mice, 83% in obese mice). Myostatin KO improved HbA 1c (6.33±0.50 vs. 10.00±1.54) in db/db mice, and fasting glucose in both lean and db/db mice, while myostatin KO had no effect on lipid metabolism. Glucose tolerance test results showed that db/db mice were insulin resistant and that myostatin KO improved insulin sensitivity in db/db mice. Obese db/db mice demonstrated an impaired microvascular vasodilation to acetylcholine that was improved by KO of myostatin. Adrenergic constriction was similar in all groups. Improvement of vasodilator capacity by myostatin KO was not attributed to vascular sensitivity to nitric oxide or changes in vascular structure and mechanics. Taken together, these data suggested that myostatin deletion in obese mice improved insulin resistance and endothelium dependent vasodilation.