Long-term skeletal muscle mitochondrial dysfunction is associated with hypermetabolism in severely burned children

Authors: PORTER, CRAIG - University Of Texas Medical Branch; HERNDON, DAVID - University Of Texas Medical Branch; BORSHEIM, ELISABET - Arkansas Children'S Nutrition Research Center (ACNC); BHATTARAI, NISHA - University Of Texas Medical Branch; CHAO, TONY - University Of Texas Medical Branch; REIDY, PAUL - University Of Texas Medical Branch; RASMUSSEN, BLAKE - University Of Texas Medical Branch; ANDERSEN, CLARK - University Of Texas Medical Branch; SUMAN, OSCAR - University Of Texas Medical Branch; SIDOSSIS, LABROS - University Of Texas Medical Branch

Submitted to: Journal of Burn Care and Rehabilitation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/1/2015
Publication Date: 1/1/2016
Citation: Porter, C., Herndon, D., Borsheim, E., Bhattarai, N., Chao, T., Reidy, P.T., Rasmussen, B.B., Andersen, C.R., Suman, O.E., Sidossis, L.S. 2016. Long-term skeletal muscle mitochondrial dysfunction is associated with hypermetabolism in severely burned children. Journal of Burn Care and Rehabilitation. 37(1):53-63. doi: 10.1097/BCR.0000000000000308.

Interpretive Summary: Burn victims loose muscle mass and function during their acute hospitalization, which translates to impaired physical function after hospital discharge. Indeed, reduced muscle mass and function are known to persist for years post injury in burn victims. Mitochondria are the cellular organelles responsible for producing energy within muscle. We have shown that mitochondrial function is depressed in burn victim at approximately 1 and 3 weeks post injury. However, the long-term impact of burns on skeletal muscle mitochondrial function remains unknown. Through our studies we found that skeletal muscle mitochondrial capacity is depressed for 1 year after burn injury; skeletal muscle mitochondrial function is depressed for 2 years after burn injury; and that skeletal muscle mitochondrial dysfunction is associated with increased metabolic rate in burn victims. Our data highlight the importance of interventions, such as exercise and drug therapy, in restoring skeletal muscle mitochondrial function in burn victims.

Technical Abstract: The long-term impact of burn trauma on skeletal muscle bioenergetics remains unknown. Here, we determined respiratory capacity and function of skeletal muscle mitochondria in healthy individuals and in burn victims for up to two years post-injury. Biopsies were collected from the m. vastus lateralis of 16 healthy men (26+/-4 years) and 69 children (8+/-5 years) with burns encompassing =30% of their total body surface area. 79 biopsies were collected from cohorts of burn victims at 2 weeks (n=18), 6 months (n=18), 12 months (n=25) and 24 months (n=18) post-burn. Mitochondrial respiration was determined in saponin-permeabilized myofiber bundles. Outcomes were modeled by analysis of variance, with differences in groups assessed by Tukey-adjusted contrasts. Burn patients were hypermetabolic for up to two years post injury. Coupled mitochondrial respiration was lower at 2 weeks (17+/-2 pmol/mg/sec, P<0.001), 6 months (41+/-4 pmol/mg/sec, P<0.05) and 12 months (35+/-3 pmol/mg/sec, P<0.001) post-burn compared to healthy controls (62+/-5 pmol/mg/sec). Coupled respiration was greater at 6, 12 and 24 months post-burn vs. 2 weeks post-burn (P<0.001). Mitochondrial ADP and oligomycin sensitivity (measures of coupling control) were lower at all time-points post-burn vs. control (P<0.05), but greater at 6, 12 and 24 months post burn vs. 2 weeks post burn (P<0.05). Muscle mitochondrial respiratory capacity remains significantly lower in burn victims for one-year post injury. Mitochondrial coupling control is diminished for up to two years post-injury in burn victims, resulting in greater mitochondrial thermogenesis. These quantitative and qualitative derangements in skeletal muscle bioenergetics likely contribute to the long-term pathophysiological stress response to burn trauma.