Dysregulation of Skeletal Muscle Mitochondrial Function following Critical Illness: a Translational Approach

Abstract

Bioenergetic failure is a significant clinical consequence of sepsis‐induced critical illness and is characterized by reduced skeletal muscle mitochondrial density, and mitochondrial dysfunction. Early activation of mitochondrial biogenesis is associated with survival and improved physical function in critically ill patients. Therefore, investigating mechanisms associated with early activation of mitochondrial biogenesis may improve targeting of future rehabilitative strategies. A rodent cecal‐ligation and puncture (CLP) model was used to mimic sepsis‐induced critical illness. The objective of the study was to determine whether CLP impaired genes implicated in mitochondrial function in the diaphragm. The CLP model involved ligation of 50% of the cecum below the ileocecal valve in adult C57BL6 mice, followed by needle puncture of the cecum resulting in mid‐grade sepsis. Mice survived for 48 hours or more, following injury. Diaphragm and limb muscles were harvested 24 hours following CLP (N=6) and following a sham CLP procedure (N=6). Gene expression of mef2c, myh1, and pgc1‐α, were significantly decreased in the diaphragm of CLP injured animals when compared to controls. In addition, ubiquitin ligases, murf1 and atrogin were increased in the diaphragm 24 hours after injury (p< 0.01). Our results indicate that sepsis‐induced critical illness significantly impacts the expression of genes implicated in mitochondrial homeostasis and atrophy. Ongoing studies will identify whether CLP injury decreases skeletal muscle mitochondrial function.Support or Funding InformationNIH grants U54 GM104940 and Department of Physiology Funds.