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Peer-reviewedCC BY 4.0Frontiers in Endocrinology

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

  • Mengxin Guan1
  • Qiong Qiong1
  • Xuejiao Cui2
  1. 1China Medical University
  2. 2Department of Endocrinology, Shengjing Hospital of China Medical University
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{guan2026thyroid,
  title = {{Thyroid FT3-FT4 axis and sarcopenia risk: an integrative perspective}},
  author = {Mengxin Guan and Qiong Qiong and Xuejiao Cui},
  journal = {Frontiers in Endocrinology},
  year = {2026},
  month = nov,
  doi = {10.3389/fendo.2026.1969246},
  url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1969246/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Thyroid FT3-FT4 axis and sarcopenia risk: an integrative perspective
AU  - Mengxin Guan
AU  - Qiong Qiong
AU  - Xuejiao Cui
PY  - 2026
DA  - 2026/11/05
JO  - Frontiers in Endocrinology
DO  - 10.3389/fendo.2026.1969246
UR  - https://www.frontiersin.org/articles/10.3389/fendo.2026.1969246/full
AB  - 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.
SN  - 1664-2392
ER  -