Thyroxine does not improve skeletal muscle regeneration after injury in aged mice

Thyroid hormone levels decrease with aging, and low thyroxine levels are correlated with sarcopenia development. While thyroid hormone stimulates myogenesis in young subjects, its effect on aged muscle regeneration is unclear. We aimed to investigate the impact of a low dose of thyroxine (T4) replacement therapy (7.5 ng/g body weight) on tibial anterior regeneration 7 days after injury by 1.2% BaCl2 injection in 24-27-month-old male mice. Our primary data suggest that regenerating aged skeletal muscle exhibits local resistance to thyroid hormone action without altering myogenic regulatory factors expression. However, T4 treatment decreases the number of central nuclei, indicative of newly formed fibers. In addition, we observed a decrease in cross-sectional area and an increase in myonuclei domain, cell death, and laminin expression in T4-treatment injured muscles. Rather than improving regeneration, T4 replacement therapy appears to induce atrophy and tissue remodeling. Our data highlight the need to understand aging physiology since thyroid hormones are crucial for muscle regeneration in young animals, although T4 replacement therapy does not improve muscle regeneration post-injury in elderly mice. This research may support clinical recommendations against treating sarcopenic patients with subclinical hypothyroidism, especially following fall-related injuries.