Arsenic exposure alters liver metabolism and accelerates skeletal muscle atrophy in female BALB/c Mice

Abstract

The liver and skeletal muscle are metabolically interconnected organs vital for maintaining systemic homeostasis. Arsenic toxicity is known to adversely affect both organs individually, yet the mechanistic link between arsenic-induced liver dysfunction and skeletal muscle deterioration remains unclear. This study aimed to investigate whether arsenic-induced alterations in hepatic metabolism are associated with changes in skeletal muscle health. BALB/c mice were divided into four groups: Control, 0.2 ppm arsenic, 2 ppm arsenic, and 20 ppm arsenic. For 30 days, sodium arsenite was administered in the drinking water ad libitum. Arsenic exposure led to elevated serum ALT and AST levels, increased hepatic lipid accumulation, and dysregulated the expression of oxidative stress defense components (Nrf2/Keap1), lipid metabolism regulators (PPAR-γ and PPAR-α), β-oxidation and lipogenic enzymes (CPT-1, and SREBP-1), as well as hepatic energy sensors (p-mTOR and p-AMPK). These hepatic changes were accompanied by oxidative stress and elevated proinflammatory cytokines (TNF-α, IL-6) in the liver and serum. Concurrently, skeletal muscle exhibited functional decline, as evidenced by decreased grip strength and elevated serum creatine kinase levels. Histological and Succinate dehydrogenase (SDH) analysis further revealed atrophy, characterized by reduced fiber cross-sectional area and a fiber-type shift from fast-twitch (Type II) to slow-twitch (Type I) fibers respectively. At the molecular level, arsenic exposure upregulated the muscle-specific ubiquitin ligases MuRF1 and atrogin-1, accompanied by NF-κB activation, indicating increased proteolysis and inflammation. Additionally, decreased irisin expression in both liver and muscle and reduced serum insulin levels indicated systemic metabolic dysregulation. Correlation analysis of inflammatory markers with indices of liver and muscle injury, together with evidence of crosstalk between these tissues, revealed significant associations. Collectively, these findings suggest that arsenic-induced hepatic disturbances may indirectly contribute to skeletal muscle wasting via systemic inflammation, supporting the possible involvement of a liver–muscle axis in arsenic toxicity.