Thyroid hormone receptor-α regulates autophagy, mitochondrial biogenesis, and fatty acid utilization in skeletal muscle

Skeletal muscle (SM) weakness occurs in hypothyroidism and resistance to thyroid hormone alpha (RTHα) 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 (TRα), 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, TRα1 PV/+ mice which expresses mutant Thra1PV gene ubiquitously, and SM-TRα1 L400R/+ mice, which expresses TRα1 L400R in a muscle-specific manner, were used in this study. Gastrocnemius muscle from TRα1 PV/+, SM-TRα1 L400R/+, and their control mice was harvested for analyses. We demonstrated that loss of TRα1 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 (LAMP1, and LAMP2) and lysosomal proteases (cathepsin B and cathepsin D). The expression of PGC1α, TFAM, and ERRα, 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 TRα1. Transcriptomic and metabolomic analyses of SM suggested that lipid catabolism was impaired, and was associated with decreased acylcarnitines and tricarboxylic acid cycle (TCA cycle) intermediates in the SM from the mouse line expressing SM-specific mutant TRα1. Our results provide new insight into TRα1-mediated cell signaling, molecular, and metabolic changes that occur in SM when TR action is impaired.