Perfluorooctane sulfonic acid (PFOS) perturbs skeletal muscle oxidative phosphorylation by a different mechanism than liver.

PFOS perturbs normal energy metabolism such as lipid metabolism; however, despite being a highly metabolic organ, skeletal muscle toxicity has not been widely studied. Skeletal muscle, a healthy body's largest metabolic organ, presents a target for PFOS-induced metabolic toxicity due to its high mitochondrial content. Therefore, we aimed to evaluate the response of skeletal muscle to PFOS in vivo and compare the responses to liver. Mice were treated with 0, 1, or 10 mg/kg/day PFOS for 21-days and gastrocnemius and liver collected. All mice exhibited a dose-dependent decrease in bodyweight following PFOS treatment; only females were susceptible to loss of muscle mass. In contrast, liver weight increased in all mice. PFOS showed significant bioaccumulation in gastrocnemius, albeit lower than the liver. Despite reduced bioaccumulation, gastrocnemius was highly sensitive to transcriptomic changes. Only 5 % of differentially expressed genes were shared between the tissues. In gastrocnemius, mitochondrial OXPHOS pathways were highly sensitive to PFOS with ETC 1 most sensitive based on GO term and KEGG pathway analysis. In liver, PPAR transcription and fatty acid metabolism were some of the more sensitive pathways. Mitochondrial respiration assays (Seahorse) confirmed that complex I and IV capacity in PFOS-treated female gastrocnemius was repressed, whereas complex II capacity was repressed by PFOS treatment in liver. An increase in fast-oxidative fibers may have provided males, in comparison to females, some compensatory protection from the effects of PFOS. These results indicate that skeletal muscle is sensitive to PFOS toxicity, and PFOS perturbs different pathways in skeletal muscle than liver.