Thyroid Hormone Status Regulates Skeletal Muscle Response to Chronic Motor Nerve Stimulation.

Although both exercise and thyroid hormone (TH) status can cause cellular and metabolic changes in skeletal muscle, the impact of TH status on exercise-associated changes is not well understood. Here, we examined the effects of TH status on muscle fiber type, cell signaling, and metabolism in a rabbit model of exercise training - chronic motor nerve stimulation (CMNS). Five rabbits were rendered hypothyroid for 7-8 weeks and three rabbits were made hyperthyroid for 2 weeks prior to CMNS of the left peroneal nerve for 10 days. We then measured markers of muscle fiber type, autophagy, and nutrient- or energy-sensing proteins, and metabolic intermediates. CMNS increased MHC-I expression in hypothyroid rabbits, whereas it was unchanged in hyperthyroid rabbits. CMNS also increased p-AMPK, p-ATGL, CPT-1α, p-Akt, GLUT4, and p-70S6K in hypothyroid rabbits. In contrast, p-AMPK and p-AKT were increased at baseline in hyperthyroid rabbits, but CMNS did not further increase them or any of the other markers. CMNS also increased TCA cycle and acylcarnitine metabolites in hypothyroid rabbits; whereas, acylcarnitines were already elevated in hyperthyroid rabbits, and were only slightly increased further by CMNS. In summary, CMNS effects on cell signaling and metabolism of skeletal muscle were more pronounced in the hypothyroid than the hyperthyroid state. Interestingly, in the hypothyroid state, CMNS caused concomitant activation of two signaling pathways that are usually reciprocally regulated - AMPK and mTOR signaling - which manifested as increased β-oxidation, MHC-I expression, and protein synthesis. Thus, our findings provide insight into the role of TH status on exercise response in muscle. Our observations suggest that TH status of patients may be an important determinant and predictor of their response to exercise training in skeletal muscle.

Duke Scholars

Author William Erle Kraus Medicine, Cardiology

Author Daniel Christopher Parker Medicine, Geriatrics

Author James Patrick White Jr. Medicine, Hematology

Author Kim Marie Huffman Medicine, Rheumatology and Immunology

Author Paul Michael Yen Medicine, Endocrinology, Metabolism, and Nutrition