Thyroid FT3-FT4 axis and sarcopenia risk: an integrative perspective

Sarcopenia, the age-related decline in muscle mass, strength, and performance, is projected to quadruple by 2050. Although endocrine dysregulation is a modifiable contributor, clinical paradigms have prioritized isolated TSH and FT4, neglecting the FT3/FT4 ratio as a metric of peripheral hormone activation. This narrative review synthesizes observational studies, four Mendelian randomization analyses, and mechanistic investigations (2015–2025) from PubMed, Web of Science and CNKI, qualitatively appraised for plausibility, consistency, and bias. Epidemiological and genetic data link elevated FT4 and reduced FT3/FT4 ratios to lower appendicular lean mass and impaired muscle function, whereas FT3 shows an inverted U-shaped relationship with muscle anabolism; genetic analyses further dissociate the muscular effects of FT3 by phenotype—protective for appendicular lean mass yet adverse for grip strength. Mild TSH elevation in older adults may reflect an adaptive response rather than pathology. Mechanistically, these converge on TRα signaling, the D2/D3 deiodinase switch, mitochondrial dynamics, and the GPT2-dependent anaplerotic axis. To reconcile these patterns, we propose a heuristic dose–response landscape mapping sarcopenia risk across four metabolic zones based on FT4 and the FT3/FT4 ratio. These findings support a shift from pituitary-centric to tissue-centric thyroid assessment, cautioning against reflexive hormonal normalization in older adults and underscoring integrated, age-stratified sarcopenia care.