Transcriptional suppression of lipid‐induced apoptosis in skeletal muscle in vivo

Lipotoxicity occurs when fatty acid (FA) delivery exceeds the storage capacity of non‐adipose tissues, causing cell dysfunction and/or death by apoptosis. FA metabolites accumulate in skeletal muscle (SM) in obesity and cause lipid‐induced apoptosis in vitro . AIM: To determine the lipotoxic effects of FAs in SM in vivo . SM lipotoxicity was investigated in 3 models of FA oversupply: C57Bl/6 mice fed a high fat diet (HFD) for 12 weeks, genetically obese ob/ob mice, and acutely via 5 h Intralipid infusion in mice. Muscles were dissected then morphological, apoptotic and autophagic markers were assessed. The Intralipid infusion increased plasma FAs 3‐fold and increased caspase 3 activity. HFD and genetic obesity induced adiposity and muscle triglyceride accumulation but did not induce apoptosis as assessed by TUNEL staining and caspase 3 activity. There was no evidence of SM regeneration or atrophy in HFD or ob/ob mice. The expression of 31 pro‐apoptotic genes were decreased by HFD. Autophagy was assessed by measuring LC3[alpha] and [beta] gene expression (conversion of [alpha] to [beta] represents autophagic activity). LC3[beta] was increased 3‐fold in ob/ob mice but there was no evidence of autophagy in HFD. While lipid‐induced apoptosis occurs in vivo , these data suggest that SM adapts to chronic lipid oversupply by decreasing pro‐apoptotic gene expression to prevent cell death. Funded by: ARC, NHMRC