Glucagon-like peptide-1 receptor (GLP-1R) agonists prevent tributyltin-induced muscle atrophy/wasting via restoring GLP-1R signaling in vitro and in mice
Journal
Ecotoxicology and Environmental Safety
Journal Volume
309
Start Page
119523
ISSN
0147-6513
Date Issued
2026-01
Author(s)
Lin, Yuan-Cheng
Lan, Kuo-Cheng
Tzeng, Huei-Ping
Wang, Ching-Chia
Chang, Ting-Yu
Liu, Shing-Hwa
Chan, Ding-Cheng
Abstract
Tributyltin (TBT), an endocrine disruptor, has been shown to exert pathological effects on skeletal muscle, though the underlying mechanisms remain incompletely understood. This study investigated the role of glucagon-like peptide-1 receptor (GLP-1R) in TBT-induced myopathy both in vitro and in vivo. GLP-1R agonists (GLP-1RAs), exendin-4 (Ex-4) and liraglutide (Lira), were tested in C2C12 myotubes (25-500 nM) exposed to TBT (0.25 μM) and in mice orally administered TBT (25 μg/kg/day) with Ex-4 (2.5 μg/kg/day) for 8 weeks. In myotubes, TBT reduced cell viability and diameter and increased apoptosis- and atrophy-related proteins, effects that were significantly mitigated by either Ex-4 or Lira. Both agents shifted myotube diameter distributions toward larger sizes, indicating attenuation of atrophy. TBT decreased GLP-1R protein expression, which was restored by Ex-4. In mice, reduced soleus muscle mass, cross-sectional area, and hindlimb grip strength, increased apoptotic and atrophy markers, and suppressed ERK and FoxO1 phosphorylation; these effects were reversed by Ex-4. GLP-1R expression in soleus muscle, downregulated by TBT, was restored with Ex-4. These findings demonstrate that GLP-1RAs protect against TBT-induced muscle wasting in vitro, with Ex-4 showing in vivo efficacy through restoration of GLP-1R expression and normalization of apoptosis- and atrophy-related signaling.
Subjects
Exendin-4
Glucagon-like peptide-1 receptor agonist
Skeletal muscle wasting
Tributyltin
Publisher
Elsevier BV
Type
journal article