Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, NA 80138 Italy.
Department of Pharmacy, University of Naples "Federico II", Naples, NA 80138 Italy.
Cell Rep. 2022 Feb 22;38(8):110409. doi: 10.1016/j.celrep.2022.110409.
Thyroid hormones (THs) are key metabolic regulators coordinating short- and long-term energy needs. In skeletal muscle, THs modulate energy metabolism in pathophysiological conditions. Indeed, hypo- and hyperthyroidism are leading causes of muscle weakness and strength; however, the metabolic pathways underlying these effects are still poorly understood. Using molecular, biochemical, and isotope-tracing approaches combined with mass spectrometry and denervation experiments, we find that THs regulate glutamine metabolism and anaplerotic fluxes by up-regulating the glutamate pyruvate transaminase 2 (GPT2) gene. In humans, GPT2 autosomal recessive mutations cause a neurological syndrome characterized by intellectual disability, microcephaly, and progressive motor symptoms. Here, we demonstrate a role of the TH/GPT2 axis in skeletal muscle in which it regulates muscle weight and fiber diameter in resting and atrophic conditions and results in protection from muscle loss during atrophy. These results describe an anabolic route by which THs rewire glutamine metabolism toward the maintenance of muscle mass.
甲状腺激素（THs）是协调短期和长期能量需求的关键代谢调节剂。在骨骼肌中，THs 在病理生理条件下调节能量代谢。事实上，甲状腺功能减退和甲状腺功能亢进是肌肉无力和力量的主要原因；然而，这些影响的代谢途径仍知之甚少。我们使用分子、生化和同位素追踪方法结合质谱和去神经实验，发现 THs 通过上调谷氨酸丙酮酸转氨酶 2（GPT2）基因来调节谷氨酰胺代谢和补料通量。在人类中，GPT2 常染色体隐性突变导致一种以智力残疾、小头畸形和进行性运动症状为特征的神经系统综合征。在这里，我们证明了 TH/GPT2 轴在骨骼肌中的作用，它在休息和萎缩状态下调节肌肉重量和纤维直径，并在萎缩过程中防止肌肉损失。这些结果描述了 THs 通过重新布线谷氨酰胺代谢来维持肌肉质量的合成途径。
