Oxidation of myosin heavy chain and reduction in force production in hyperthyroid rat soleus Short title: Hyperthyroid-induced force reduction and oxidative stress
چکیده
ABSTRUCT We tested the hypothesis that a force reduction in hyperthyroid rat soleus muscle would be associated with oxidative modification in myosin heavy chain (MHC). Daily injection of thyroid hormone (3,5,3'-triiodo-L-thyronine, T 3) for 21 days depressed isometric forces of whole soleus muscle across a range of stimulus frequencies (P < 0.01). In fiber bundles, hyperthyroidism also led to pronounced reductions (P < 0.01) in both K +-and 4-chloro-m-cresol-induced contracture forces. The degrees of the reductions were similar between these two contractures that were induced by distinct reagents. Treatment with T 3 elicited a significant decrease (ዊ14%; P < 0.05) in the relative content of MHC contained in myofibrillar proteins. The content of carbonyl groups in myofibrillar protein extracts was elevated (P < 0.05) by ዊ50% in T 3-treated muscles. Immunoblot analyses on T 3-treated muscles showed a greater increase (106%; P < 0.05) of the carbonyl content in MHC than in myofibrillar protein extracts. These data suggest that in hyperthyroidism, the decrease in force production of skeletal muscles may stem primarily from failure in myofibrillar protein function resulting from oxidative modification of MHC. Introduction Despite the well-accepted view that loss of muscle strength and exercise intolerance are prominent clinical features of hyperthyroid patients (33), the mechanisms underlying the depressed capacity of contractile function in skeletal muscle remain incompletely understood. Although protein degradation due to accelerated proteolysis has been found in skeletal muscle of patients with hyperthyroidism (2, 38), it seems unlikely that the protein loss contributes only to the muscle weakness in hyperthyroid skeletal muscles. Based mainly on clinical examinations, muscle strength has been shown to decrease by 40-100%, whereas muscle mass only reduced by approximately 20% in hyperthyroidism (29, 46), suggesting that the observed reduction in force may result not only from muscle atrophy, but also from the failures in the excitation-contraction (EC) coupling process. In contrast to clinical observations, the effects of thyroid hormone on isometric properties in the animal model are controversial. A hyperthyroid state has been reported to consistently decrease the isometric twitch force (12, 13, 26, 44), but to either decrease (44) or maintain the maximum tetanic force at control levels (12, 13, 26). This discordance seems likely to be related to the dosage of thyroid hormone administered to the animals. For example, Merican and coworkers (26, 44) have studied the effects of two doses of thyroxine treatment on the isometric properties of cat …