Thyroid-stimulating hormone exacerbates mitochondrial energy dysregulation and cardiac remodeling with involvement of the AMPK/PGC-1α pathway.

BACKGROUND AND AIMS: Subclinical hypothyroidism (SCH) is linked to the progression of heart failure (HF); however, the underlying mechanisms remain unclear. This study aimed to investigate the role of thyroid-stimulating hormone (TSH) in the regulation of HF and myocardial energy metabolism.

METHODS

In vitro, cardiomyocytes were treated with TSH to assess pathological stress markers and mitochondrial energy metabolism. In vivo, a SCH model was established in thyrocyte-specific TSHR knockout mice, with concurrent isoproterenol (ISO)-induced HF. Serum FT4 and TSH levels, cardiac function, and myocardial energy metabolism (ATP levels, mitochondrial ultrastructure, key metabolic enzymes) were evaluated. Cardiomyocyte-specific TSHR knockout mice were used to confirm findings, and the involvement of the AMPK/PGC-1α pathway was investigated in vitro.

RESULTS

In vitro, TSH treatment increased the expression of pathological stress markers in cardiomyocytes. It also induced alterations in energy substrates, decreased ATP levels, and reduced mitochondrial membrane potential. In vivo, compared to the ISO group, mice in the SCH + ISO group exhibited more severe cardiac structural damage and functional impairment, accompanied by aggravated energy metabolism remodeling and mitochondrial dysfunction-characterized by lower ATP content, exacerbated mitochondrial ultrastructural damage, increased glycolysis, and decreased aerobic glucose oxidation. Notably, cardiomyocyte-specific TSHR knockout mitigated cardiac damage and metabolic remodeling in HF mice induced by ISO. Further mechanistic studies suggest that the AMPK/PGC-1α signaling pathway is involved in the regulation of TSH-mediated mitochondrial energy metabolism and cardiac remodeling.

CONCLUSION

Our findings indicate that SCH exacerbates HF progression and further implicate TSH/TSHR signaling in the regulation of myocardial energy metabolism.