Thyroid Hormone Receptor Isoforms Alpha and Beta Play Convergent Roles in Muscle Physiology and Metabolic Regulation

Abstract

Skeletal muscle is a key energy-regulating organ, skilled in rapidly boosting the rate of energy production and substrate consumption following increased workload demand. The alteration of skeletal muscle metabolism is directly associated with numerous pathologies and disorders. Thyroid hormones (THs) and their receptors (TRs, namely, TRα and TRβ) exert pleiotropic functions in almost all cells and tissues. Skeletal muscle is a major THs-target tissue and alterations of THs levels have multiple influences on the latter. However, the biological role of THs and TRs in orchestrating metabolic pathways in skeletal muscle has only recently started to be addressed. The purpose of this paper is to investigate the muscle metabolic response to TRs abrogation, by using two different mouse models of global TRα- and TRβKO. In line with the clinical features of resistance to THs syndromes in humans, characterized by THRs gene mutations, both animal models of TRs deficiency exhibit developmental delay and mitochondrial dysfunctions. Moreover, using transcriptomic and metabolomic approaches, we found that the TRs–THs complex regulates the Fatty Acids (FAs)-binding protein GOT2, affecting FAs oxidation and transport in skeletal muscle. In conclusion, these results underline a new metabolic role of THs in governing muscle lipids distribution and metabolism.

Aberrant expression of thyroidal hormone receptor α exasperating mitochondrial dysfunction induced sarcopenia in aged mice

“…Considering the lower level of TRα observed in our study and its vital role in maintaining mitochondrial function according to previous studies [16,17], we hypothesized that aging related muscle loss might result from the loss of TRα.…”

“…Mitochondrial dysfunction had intimate relationship with senescence and SM degeneration. TH signaling pathway has been proved to regulate mitochondrial quality control systems including mitochondrial dynamics and mitophagy, as well as mitochondrial function in SM [13][14][15][16][17]. However, the role of TRα in regulating mitochondrial quality control systems and mitochondrial function during aging is still unclear.…”

Association between physical activity and thyroid function in American adults: a survey from the NHANES database

“…THs can also influence the levels of PA. Agitation is a characteristic of hyperthyroidism while hypothyroid patients tend to be less active [2]. TH receptors TRα and TRβ are both critical regulators of muscular genes and alterations in TRs are associated with muscle dysfunctions in mice and humans [31,32]. In a study in 2023, Miro et al have indicated that THs alter the proportion of saturated and unsaturated fatty acids (FAs) in Skeletal muscle (SKM) lipids membrane, and regulated the lipid content of muscle fibres, thereby affecting physical exercise performance [33].…”

Cardiovascular and Neuronal Consequences of Thyroid Hormones Alterations in the Ischemic Stroke

“…Central and local thyroid hormones dysfunctions are frequent conditions reported in case of ischemic events. THs are involved in several physiological processes and, in particular, are important players in driving the development and the maturation of multiple tissues through genomic and non-genomic actions [ 23 , 24 , 67 , 92 , 115 , 123 ]. It has long been known that THs have a variety of effects on the cardiovascular system and brain development.…”

“…The complex relationship between the thyroid hormones serum concentration and the insurgence, severity and recovery after stroke remains controversial because thyroid hormones exert both neurotoxic and neuroprotective effects [ 20 , 21 ]. Thyroid hormones (THs), the prohormone L-Thyroxine (T4, or 3,3′,5,5′-tetraiodo-L-thyronine) and the active form Triiodothyronine (T3, or 3,3′,5-triiodo-L-thyronine), are pivotal determinants of the energy metabolism and the homeostatic control of basically every body tissue [ 22 , 23 , 24 ]. While the systemic THs concentration depends on a central control exerted by the Hypothalamus-Pituitary-Thyroid (HPT) axis, their intracellular levels are finely tuned by a complex network of crucial regulators of THs signaling: the plasma membrane transporters, mainly MCT8 and MCT10, which mediate the THs cellular uptake [ 25 ]; the different isoforms of THs receptors, TRα and TRβ that, through the binding to THs, regulate the transcription of TH target genes [ 26 ], and the deiodinase enzymes [ 27 ].…”