# Hypothyroidism impairs skeletal muscle regeneration after injury by altering myogenic and nonmyogenic pathways

## TL;DR

Hypothyroidism hinders muscle repair after injury by disrupting cell cycles, reducing muscle cell diversity, and altering immune and fibro-adipogenic processes.

## Contribution

This study reveals novel effects of hypothyroidism on myogenic heterogeneity and tissue repair through dual modes of triiodothyronine action.

## Key findings

- Hypothyroid muscles showed smaller myofibers and a shift to slower oxidative fiber types during regeneration.
- Hypothyroidism reduced myogenic-lineage diversity and delayed cell cycle progression in muscle stem cells.
- Altered nonmyogenic dynamics included elevated fibro-adipogenic progenitors and persistent proinflammatory macrophages.

## Abstract

Thyroid hormone signaling is an essential regulator of skeletal muscle development, function, and metabolism, yet the specific signaling pathways required for muscle regeneration are not yet defined. We used scRNA-seq and the FUCCI (fluorescent ubiquitination-based cell cycle indicator) reporter mouse model to examine how hypothyroidism impacts repair processes after cardiotoxin-induced injury in mice. During regeneration, and up to 2 months after injury, hypothyroid muscles displayed smaller myofibers and a shift to slower oxidative fiber types. scRNA-seq of tibialis anterior muscle during regeneration revealed that hypothyroidism reduced myogenic-lineage diversity. Cell cycle analysis confirmed delayed cell cycle progression at 5 and 14 days after injury, with skeletal muscle stem cells stalled at the G1/S transition, hindering differentiation. Transcriptomic data revealed altered nonmyogenic dynamics, including elevated activated fibro-adipogenic progenitors (FAPs) early in repair and persistent proinflammatory macrophages. Integrative regulon and ligand-receptor analysis further demonstrated that triiodothyronine acted through dual modes: a direct transcriptional control of myogenic cell cycle and oxidative programs and an indirect paracrine remodeling mediated by FAP and immune signaling networks. This study identified what we believe to be novel effects of hypothyroidism on myogenic heterogeneity and impaired tissue repair, offering insights into muscle-wasting mechanisms relevant to hypothyroidism-associated myopathy and sarcopenia.

Hypothyroidism impairs muscle regeneration by disrupting cell cycle progression, reducing myogenic diversity, and by altering fibro-adipogenic and immune cell dynamics.