Thyroid Hormone Receptor α Regulates Autophagy, Mitochondrial Biogenesis, and Fatty Acid Use in Skeletal Muscle

Skeletal muscle (SM) weakness occurs in hypothyroidism and resistance to thyroid hormone alpha (RTH alpha) syndrome. However, the cell signaling and molecular mechanism(s) underlying muscle weakness under these conditions is not well understood. We thus examined the role of thyroid hormone receptor alpha (TR alpha), the predominant TR isoform in SM, on autophagy, mitochondrial biogenesis, and metabolism to demonstrate the molecular mechanism(s) underlying muscle weakness in these two conditions. Two genetic mouse models were used in this study: TR alpha 1(PV/+) mice, which express the mutant Thra1PV gene ubiquitously, and SM-TR alpha 1(L400R/+) mice, which express TR alpha 1(L400R) in a muscle-specific manner. Gastrocnemius muscle from TR alpha 1(PV/+), SM-TR alpha 1(L400R/+), and their control mice was harvested for analyses. We demonstrated that loss of TR alpha 1 signaling in gastrocnemius muscle from both the genetic mouse models led to decreased autophagy as evidenced by accumulation of p62 and decreased expression of lysosomal markers (lysosomal-associated membrane protein [LAMP]-1 and LAMP-2) and lysosomal proteases (cathepsin B and cathepsin D). The expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1 alpha), mitochondrial transcription factor A (TFAM), and estrogen-related receptor alpha (ERR alpha), key factors contributing to mitochondrial biogenesis as well as mitochondrial proteins, were decreased, suggesting that there was reduced mitochondrial biogenesis due to the expression of mutant TR alpha 1. Transcriptomic and metabolomic analyses of SM suggested that lipid catabolism was impaired and was associated with decreased acylcarnitines and tricarboxylic acid cycle intermediates in the SM from the mouse line expressing SM-specific mutant TR alpha 1. Our results provide new insight into TR alpha 1-mediated cell signaling, molecular, and metabolic changes that occur in SM when TR action is impaired.

Automated summary

The study revealed that loss of TR alpha 1 signaling in skeletal muscle leads to decreased autophagy, reduced mitochondrial biogenesis, and impaired lipid catabolism, resulting in muscle weakness.