Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation

Abstract

Metabolic derangements are a clinically significant complication of major trauma (e.g., burn injury) and include various aspects of metabolism, such as insulin resistance, muscle wasting, mitochondrial dysfunction and hyperlactatemia. Nonetheless, the molecular pathogenesis and the relation between these diverse metabolic alterations are poorly understood. We have previously shown that burn increases farnesyltransferase (FTase) expression and protein farnesylation and that FTase inhibitor (FTI) prevents burn-induced hyperlactatemia, insulin resistance, and increased proteolysis in mouse skeletal muscle. In this study, we found that burn injury activated mTORC1 and hypoxia-inducible factor (HIF)-1α, which paralleled dysfunction, morphological alterations (i.e., enlargement, partial loss of cristae structure) and impairment of respiratory supercomplex assembly of the mitochondria, and ER stress. FTI reversed or ameliorated all of these alterations in burned mice. These findings indicate that these burn-induced changes, which encompass various aspects of metabolism, may be linked to one another and require protein farnesylation. Our results provide evidence of involvement of the mTORC1-HIF-1α pathway in burn-induced metabolic derangements. Our study identifies protein farnesylation as a potential hub of the signaling network affecting multiple aspects of metabolic alterations after burn injury and as a novel potential molecular target to improve the clinical outcome of severely burned patients.

Coenzyme Q10 protects against burn‐induced mitochondrial dysfunction and impaired insulin signaling in mouse skeletal muscle

“…The mice were housed in a pathogen‐free animal facility with 12‐h light/dark cycles at 25 °C and fed with AIN‐93M (Research Diets, New Brunswick, NJ, USA). Burn injury was produced as described previously . Starting at 2 h after burn or sham‐burn, the mice were treated with reduced form of CoQ10 (ubiquinol) provided by Kaneka Nutrients Corp. (Pasadena, TX, USA) [40 mg·kg −1 , subcutaneous injection (SC), b.i.d.]…”

“…Seahorse XFp Extracellular Flux Analyzer (Seahorse Bioscience, North Billerica, MA, USA) was used to measure mitochondrial oxygen consumption rate (OCR) as an indicator of mitochondrial respiration. As described previously, we used fresh rectus abdominis muscle . Measurement of mitochondrial respiration was performed as described previously .…”

“…As described previously, we used fresh rectus abdominis muscle . Measurement of mitochondrial respiration was performed as described previously .…”

“…Previous studies have shown that a decrease in the activity of complex I, a major component of the mitochondrial electron transport chain in skeletal muscle, is associated with the severity of septic shock . Severe burn injury causes mitochondrial dysfunction in multiple organs, including skeletal muscle . Therefore, improving mitochondrial function is thought to be a reasonable approach to ameliorating burn injury‐induced metabolic derangements and organ dysfunction.…”

“…We have previously shown that burn induces mitochondrial dysfunction and insulin resistance in skeletal muscle of mice . We hypothesized that reduced form of CoQ10 (ubiquinol) has protective effects against burn injury‐induced mitochondrial dysfunction and insulin resistance in mouse skeletal muscle.…”