Protective roles of autophagy in sepsis‐induced skeletal muscle dysfunction, metabolic derangements and mortality

Abstract

RationaleSepsis‐induced skeletal muscle dysfunction contributes to physical disability, and increased mortality in intensive care unit patients. Autophagy is a catabolic process by which cells degrade their own components. Recent studies indicate that sepsis triggers sustained induction of autophagy in skeletal muscles; however, the impact of autophagy on sepsis‐induced contractile and metabolic dysfunctions remains unclear. In this study, we evaluated the functional importance of autophagy in sepsis‐induced skeletal muscle dysfunction.MethodsSelective inhibition of autophagy in skeletal muscles was accomplished by cross breeding floxed Atg7 mice (Atg7f/f) with those expressing HSA‐Cre‐ERT2. Cre induction was achieved by feeding Tamoxifen. Control mice were Atg7f/f‐HSA‐Cre‐ERT2 without Tamoxifen feeding. Sepsis was induced by the cecal ligation and perforation (CLP) procedure and animals were examined after 48 and 144 hours of sepsis. Animals undergoing sham procedure served as control.ResultsDeletion of Atg7 in skeletal muscle had a major impact on sepsis‐induced loss of body weight and muscle mass as indicated by worsening of body weight loss, more severe sepsis‐induced skeletal muscle atrophy and further decline in muscle contractility in mice with Atg7 deletions vs. those with intact Atg7 undergoing sepsis for 48 hours. In additions, body weight loss, hypoglycaemia and mortality were more severe over a 144 hours period in mice with Atg7 deletion as compared to those with intact Atg7. These results suggest that induction of autophagy in septic skeletal muscles play a protective role against sepsis‐induced mortality. Furthermore, sepsis had no major effect on limb muscle mitochondrial respiration in animals with intact muscle Atg7 while those with deleted muscle Atg7 showed significant impairments of limb muscle mitochondrial respiration both in the sham and septic conditions. Finally, significant upregulation of ubiquitin E3 ligases (Atrogin‐1 and MuRF1) was observed in septic muscles. Deletion of muscle Atg7 had no effect on this response when measured after 48 hours of sepsis.ConclusionWe conclude that autophagy plays a protective role by preserving muscle mitochondrial quality and function and that autophagy inhibition in skeletal muscles worsens sepsis‐induced loss of body weight and muscle atrophy possibly due to exaggerated responses to catabolic stimuli triggered by sepsis. Our results also indicate that autophagy in septic skeletal muscles play a protective role against sepsis‐induced metabolic derangements and mortality.Support or Funding InformationThis study is funded by grants from the Canadian Institutes of Health Research. Gilles Gouspillou salary support is provided by a FQRS Chercheur Boursier Junior 1 Award. Jean‐Philippe Leduc‐Gaudet is supported by CIHR Vanier Doctoral Scholarship.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.