title: Hypermetabolism and hypercatabolism of skeletal muscle accompany mitochondrial stress following severe burn trauma.
abstract: Burn trauma results in prolonged hypermetabolism and skeletal muscle wasting. How hypermetabolism contributes to muscle wasting in burn patients remains unknown. We hypothesized that oxidative stress, cytosolic protein degradation, and mitochondrial stress as a result of hypermetabolism contribute to muscle cachexia postburn. Patients (n = 14) with burns covering >30% of their total body surface area were studied. Controls (n = 13) were young healthy adults. We found that burn patients were profoundly hypermetabolic at both the skeletal muscle and systemic levels, indicating increased oxygen consumption by mitochondria. In skeletal muscle of burn patients, concurrent activation of mTORC1 signaling and elevation in the fractional synthetic rate paralleled increased levels of proteasomes and elevated fractional breakdown rate. Burn patients had greater levels of oxidative stress markers as well as higher expression of mtUPR-related genes and proteins, suggesting that burns increased mitochondrial stress and protein damage. Indeed, upregulation of cytoprotective genes suggests hypermetabolism-induced oxidative stress postburn. In parallel to mtUPR activation postburn, mitochondrial-specific proteases (LONP1 and CLPP) and mitochondrial translocases (TIM23, TIM17B, and TOM40) were upregulated, suggesting increased mitochondrial protein degradation and transport of preprotein, respectively. Our data demonstrate that proteolysis occurs in both the cytosolic and mitochondrial compartments of skeletal muscle in severely burned patients. Increased mitochondrial protein turnover may be associated with increased protein damage due to hypermetabolism-induced oxidative stress and activation of mtUPR. Our results suggest a novel role for the mitochondria in burn-induced cachexia.
authors.affiliation: Metabolism Unit, Shriners Hospitals for Children, Galveston, Texas; Department of Surgery, University of Texas Medical Branch, Galveston, Texas; joogunbi@utmb.edu.
authors.forename: John O
authors.initials: JO
authors.lastname: Ogunbileje
authors.affiliation: Metabolism Unit, Shriners Hospitals for Children, Galveston, Texas; Department of Surgery, University of Texas Medical Branch, Galveston, Texas;
authors.forename: Craig
authors.initials: C
authors.lastname: Porter
authors.affiliation: Metabolism Unit, Shriners Hospitals for Children, Galveston, Texas; Department of Surgery, University of Texas Medical Branch, Galveston, Texas;
authors.forename: David N
authors.initials: DN
authors.lastname: Herndon
authors.affiliation: Metabolism Unit, Shriners Hospitals for Children, Galveston, Texas; Department of Surgery, University of Texas Medical Branch, Galveston, Texas;
authors.forename: Tony
authors.initials: T
authors.lastname: Chao
authors.affiliation: Metabolism Unit, Shriners Hospitals for Children, Galveston, Texas; Department of Surgery, University of Texas Medical Branch, Galveston, Texas;
authors.forename: Doaa R
authors.initials: DR
authors.lastname: Abdelrahman
authors.affiliation: Metabolism Unit, Shriners Hospitals for Children, Galveston, Texas; Department of Nutrition and Metabolism, University of Texas Medical Branch, Galveston, Texas;
authors.forename: Anastasia
authors.initials: A
authors.lastname: Papadimitriou
authors.affiliation: Metabolism Unit, Shriners Hospitals for Children, Galveston, Texas;
authors.forename: Maria
authors.initials: M
authors.lastname: Chondronikola
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Zimmers
authors.affiliation: Department of Nutrition and Metabolism, University of Texas Medical Branch, Galveston, Texas;
authors.forename: Paul T
authors.initials: PT
authors.lastname: Reidy
authors.affiliation: Department of Nutrition and Metabolism, University of Texas Medical Branch, Galveston, Texas;
authors.forename: Blake B
authors.initials: BB
authors.lastname: Rasmussen
authors.affiliation: Metabolism Unit, Shriners Hospitals for Children, Galveston, Texas; Department of Surgery, University of Texas Medical Branch, Galveston, Texas; Department of Kinesiology and Health, Rutgers University, New Brunswick, New Jersey; and Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey.
authors.forename: Labros S
authors.initials: LS
authors.lastname: Sidossis
mesh_terms: D049069:ATP-Dependent Proteases / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D001830:Body Surface Area; D002056:Burns / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D002100:Cachexia / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D049071:Endopeptidase Clp / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008660:Metabolism; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D018384:Oxidative Stress; D010101:Oxygen Consumption; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D049069:ATP-Dependent Proteases; D049071:Endopeptidase Clp; D000076222:Mechanistic Target of Rapamycin Complex 1; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D009124:Muscle Proteins; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; C569163:TIMM17B protein, human; C438387:TIMM23 protein, human; C000595973:LONP1 protein, human; C568646:ClpP protein, human; C400783:TOMM40 protein, human
keywords: burn injury; cachexia; hypermetabolism-induced oxidative stress; mitochondria proteases; mitochondrial unfolded protein response