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

We evaluated PFOS metabolic toxicity in skeletal muscle where not much is known and then compared it to liver metabolic toxicity as measured by bioaccumulation, sarcopenia (muscle loss), RIFS (Respirometry in Frozen Samples; OXPHOS in mitochondria), and RNAseq - GO and KEGG. Skeletal muscle is a healthy body’s largest metabolic organ and therefore presents a target for PFOS-induced metabolic toxicity due to its high mitochondrial content. Mice were treated with 0, 1, or 10 mg/kg/day PFOS for 21-days and gastrocnemius and liver collected. We investigated responses of skeletal muscle to PFOS in vivo and compare the responses of skeletal muscle to liver. All mice exhibited a dose-dependent decrease in bodyweight following PFOS treatment; only females were susceptible to a statistically significant loss of skeletal muscle mass. In contrast, liver weight and hepatosomatic index increased in all mice. PFOS showed significant bioaccumulation in skeletal muscle, albeit lower than the liver. Despite lower bioaccumulation, skeletal muscle was highly sensitive to transcriptomic changes with large differences between skeletal muscle and liver. Only 5% of differentially expressed genes were shared between the tissues. Mitochondrial OXPHOS pathways were highly sensitive to PFOS with ETC 1 most sensitive based on GO term and KEGG pathway analysis. OXPHOS was not significantly different via RNAseq/GO/KEGG in liver; instead PPAR transcription and fatty acid metabolism were some of the more sensitive pathways. Mitochondrial activity assays confirmed that complex I and IV capacity in PFOS-treated female skeletal muscle was repressed. In contrast, complex II capacity was repressed by PFOS treatment in liver. These results indicate that skeletal muscle is sensitive to PFOS toxicity and PFOS perturbs different pathways in skeletal muscle than liver.本研究针对鲜有研究报道的骨骼肌的全氟辛烷磺酸（PFOS）代谢毒性展开评估，并以生物蓄积、肌肉减少症（sarcopenia，又称肌肉流失）、RIFS（冷冻样品呼吸测定法；线粒体氧化磷酸化检测）以及RNA测序（RNAseq）-基因本体论（GO）、京都基因与基因组百科全书（KEGG）为检测指标，将其与肝脏代谢毒性进行对比。骨骼肌是健康机体最大的代谢器官，且线粒体含量丰富，因此成为PFOS诱导代谢毒性的靶标组织。本研究以小鼠为模型，以0、1、10 mg/kg/天的剂量持续21天给予PFOS暴露，随后采集腓肠肌与肝脏组织。本研究在体内环境下探究了骨骼肌对PFOS的应答反应，并对比了骨骼肌与肝脏的应答差异。所有PFOS暴露小鼠均出现体重随暴露剂量升高而降低的剂量依赖性变化；仅雌性小鼠出现具有统计学显著性的骨骼肌重量流失。与之相反，所有小鼠的肝脏重量及肝体比均出现升高。PFOS可在骨骼肌中发生显著生物蓄积，尽管其蓄积水平低于肝脏。尽管生物蓄积水平较低，骨骼肌对转录组变化的敏感性却极高，且骨骼肌与肝脏的转录应答差异显著。两组组织间仅有5%的差异表达基因存在交集。基于GO与KEGG通路分析，线粒体氧化磷酸化（OXPHOS）通路对PFOS的敏感性极高，其中电子传递链复合物I（ETC 1）的敏感性最强。肝脏组织的OXPHOS通路在RNAseq、GO及KEGG分析中均未出现显著性变化；取而代之的是，过氧化物酶体增殖物激活受体（PPAR）转录通路与脂肪酸代谢通路为肝脏中较为敏感的通路之一。线粒体活性检测实验证实，经PFOS暴露的雌性小鼠骨骼肌中的复合物I与复合物IV活性受到抑制。与之相反，PFOS暴露会抑制肝脏中的复合物II活性。上述结果表明，骨骼肌对PFOS毒性具有较高敏感性，且PFOS在骨骼肌与肝脏中干扰的通路存在显著差异。