High-Fat Diet Induced Obesity Increases Serum Myostatin, but Does Not Accelerate Skeletal Muscle Atrophy

Abstract

Myostatin is a potent negative regulator of muscle mass, i.e. high levels of myostatin induce loss of muscle. Surprisingly, severely obese humans and obese mice have elevated levels of serum myostatin, but the role of myostatin in controlling muscle mass during obesity is largely unknown. The aim of this study is to determine if obesity induced by a high-fat diet will decrease muscle mass or sensitize muscles to other factors that induce muscle atrophy. Thirty male C57BL/6 mice were divided into three groups; 12-wk control diet (CD), 9-wk control diet then 3-wk high-fat diet (3wHF), and 12-wk high-fat diet (12wHF). At 10 weeks with each diet, the left sciatic nerve was cut (surgical denervation, a model of nerve damage), and contralateral sham operated. At 12 weeks, EDL, soleus, tibialis anterior (TA), plantaris, and gastrocnemius muscles were excised and weighed; body composition was measured by MRI; and serum myostatin was measured by ELISA. The EDL and soleus muscles were incubated and rates of protein degradation were determined by the net amount of tyrosine released. The TA muscles were cross-sectioned and mean fiber area estimated. As expected, the 12wHF resulted in a profound increase in fat mass (785%), with less in 3wHF (541%) and CD (216%). The concentration of myostatin in serum was between 1.5 to 2 fold higher (p [less than or equal to] 0.05) in the 12wHF group (705 pg/ml ± 79) than the 3wHF (420 pg/ml ± 36) and CD (316 pg/ml ± 18). In spite of this, there were no significant differences in muscle mass of the innervated muscles between diets. The percent atrophy due to denervation ranged from 15 to 39%, depending on the muscle, but there were no significant differences among diet groups, with the exception of greater atrophy (p [less than or equal to] 0.05) of the soleus muscle in the 3wHF group (26% versus 16% for CD and 15% for 12wHF). The rate of protein degradation was ~55 [eta]mol/g/hr for the innervated EDL muscles and ~75 [eta]mol/g/hr for the innervated soleus muscles. No significant differences existed between diet groups for either muscle. There were no significant differences between the diet groups for the rate of protein degradation of the denervated EDL muscles, but the rate of protein degradation for the denervated soleus muscle of the 3wkHF group was 30% faster than the CD and 12wkHF groups in accordance with the muscle mass findings. No significant differences in mean fiber area were found between diet groups among the innervated or denervated TA muscles. In summary, muscles of mice on a 12-week high-fat diet are exposed to higher myostatin but have the same mass and atrophy at the same rate as mice fed a control diet. This demonstrates that obesity may cause muscles to become resistant to the catabolic actions of myostatin.