| RRC ID |
87522
|
| Author |
Aguiari P, Villani V, Liu YY, Carraro G, Brent GA, Perin L, Milanesi A.
|
| Title |
Hypothyroidism impairs skeletal muscle regeneration after injury by altering myogenic and nonmyogenic pathways.
|
| Journal |
JCI Insight
|
| 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.
|
| Volume |
11(6)
|
| Published |
2026-3-23
|
| DOI |
10.1172/jci.insight.197761
|
| PII |
197761
|
| PMID |
41869726
|
| PMC |
PMC13043096
|
| MeSH |
Animals
G1 Phase Cell Cycle Checkpoints
Hypothyroidism* / complications
Hypothyroidism* / metabolism
Hypothyroidism* / physiopathology
Male
Mice
Muscle, Skeletal* / immunology
Muscle, Skeletal* / injuries
Muscle, Skeletal* / physiopathology
Muscular Diseases* / etiology
Regeneration*
Skeletal Muscle Enlargement*
|
| Resource |
| Mice |
RBRC06511 |
