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

Ucci Ucci,Virili Virili,Moresi Moresi,Russi Russi,Cammarata Cammarata,Verga-Falzacappa Verga-Falzacappa,Adamo Adamo,Renzini Renzini,Cavioli Cavioli,Santaguida Santaguida,Centanni Centanni,Mangialardo Mangialardo

doi:10.3390/ijms20225754

Ucci Ucci, Virili Virili + Show 10 more

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https://doi.org/10.3390/ijms20225754

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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.

Highlights

Thyroid hormones (THs), T3 and T4, play critical roles in growth, differentiation, and metabolism
With the aim of defining the role of thyroid hormone in starvation-induced skeletal muscle atrophy, adult mice were randomly divided into four groups: half of them were starved (STV) for 48 h, while the rest were fed ad libitum as controls; in each condition, mice were treated with daily intraperitoneal injections of either T3 [100 μg/kg BW], or vehicle in controls, as previously done [39]
The expression of all these genes was significantly modulated in T3-treated mice (Table 1)

Summary

Introduction

Thyroid hormones (THs), T3 and T4, play critical roles in growth, differentiation, and metabolism. They enter the cell through molecular transporters [1] and bind thyroid receptors (TRs), which classically act as transcription factors [2]. T3-dependent activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been evidenced in various cell types, leading to cell death prevention in many organs [5,6,7,8]. The T3-mediated Akt activation ameliorates pancreatic islets function and vitality in both ex vivo and in vivo models [9,10]. Our group recently highlighted the mitogenic and antiapoptotic T3 action on granulosa cells and tenocytes [8,11,12]

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