Thyroid Hormone Protects from Fasting-Induced Skeletal Muscle Atrophy by Promoting Metabolic Adaptation

Abstract

Thyroid hormones regulate a wide range of cellular responses, via non-genomic and genomic actions, depending on cell-specific thyroid hormone transporters, co-repressors, or co-activators. Skeletal muscle has been identified as a direct target of thyroid hormone T3, where it regulates stem cell proliferation and differentiation, as well as myofiber metabolism. However, the effects of T3 in muscle-wasting conditions have not been yet addressed. Being T3 primarily responsible for the regulation of metabolism, we challenged mice with fasting and found that T3 counteracted starvation-induced muscle atrophy. Interestingly, T3 did not prevent the activation of the main catabolic pathways, i.e., the ubiquitin-proteasome or the autophagy-lysosomal systems, nor did it stimulate de novo muscle synthesis in starved muscles. Transcriptome analyses revealed that T3 mainly affected the metabolic processes in starved muscle. Further analyses of myofiber metabolism revealed that T3 prevented the starvation-mediated metabolic shift, thus preserving skeletal muscle mass. Our study elucidated new T3 functions in regulating skeletal muscle homeostasis and metabolism in pathological conditions, opening to new potential therapeutic approaches for the treatment of skeletal muscle atrophy.

Associations between low muscle mass and clinical characteristics of health population in China

“…Specifically, T3 has been shown to counteract muscle wasting induced by starvation. Yet, it does not inhibit the activation of primary catabolic pathways, ie, the ubiquitin-proteasome or the autophagy-lysosomal systems, nor does it promote the synthesis of new muscle in muscles that are starved [ 19 ]. Secondly, some studies have indicated that subclinical hyperthyroidism-but not subclinical hypothyroidism-impacts muscle mass and strength in the older adult.…”

miR-27b-3p Attenuates Muscle Atrophy by Targeting Cbl-b in Skeletal Muscles

“…In terms of nutritional support, protein supplementation can promote skeletal muscle protein synthesis under disused conditions and inhibit protein breakdown [ 47 , 48 , 49 ]. Although there are many promising therapeutic targets for treating muscle atrophy, it has been reported that the thyroid hormone can protect fasting-induced skeletal muscle atrophy by promoting metabolic adaptation [ 50 ]. However, no drug has been clinically proven to be safe.…”

Fecal thyroid hormone metabolites in wild ungulates: a mini-review

“…Most of the circulating T3 originates at peripheral levels from T4 conversion; T3 is more biologically active and potent than T4 ( 28 ) but the latter has a longer blood half-life ( 29 ). It enters the cell through molecular transporters and binds thyroid receptors (TRs), which classically act as transcription factors ( 30 ).…”