Skeletal Muscle Mitochondrial Function is Determined by Burn Severity, Sex, and Sepsis, and is Associated With Glucose Metabolism and Functional Capacity in Burned Children

Background: Restoring normal mitochondrial function represents a new target for strategies aimed at mitigating the stress response to severe burn trauma and hastening recovery. Our objective was to investigate the determinants of skeletal muscle mitochondrial respiratory capacity and function and its association with glucose metabolism and functional capacity in burned children. Methods: Data from burned children enrolled in the placebo arm of an ongoing prospective clinical trial were analyzed. Mitochondrial respiratory capacity was determined in permeabilized myofibers by high-resolution respirometry on at least one occasion per participant. In subsets of patients, glucose kinetics and cardiorespiratory fitness (VO2peak) were also determined. Mixed multiple regression models were used to identify the determinants of mitochondrial respiratory function and to assess the relationship between mitochondrial respiration and both glucose control and functional capacity (VO2peak). Main results: Increasing full-thickness burn size was associated with greater adjusted coupled (ATP-producing) respiration, adjusted for age, sex, sepsis, and time of testing (P < 0.01; n = 55, obs = 97). Girls had on average 23.3% lower coupled respiration (adjusted mean and 95% confidence of interval [CI], −7.1; −12.6 to −1.7 pmol/s/mg; P < 0.025) and 29.8% lower respiratory control than boys (adjusted mean and 95% CI, −0.66; −1.07 to −0.25; P < 0.01; n = 55, obs = 97). The presence of sepsis was associated with lower respiration coupled to ATP production by an average of 25.5% compared with nonsepsis (adjusted mean and 95% CI, −6.9; −13.0 to −0.7 pmol/s/mg; P < 0.05; n = 55, obs = 97), after adjustment for age, sex, full-thickness burn size, and time of testing. During a hyperinsulinemic euglycemic clamp, hepatic glucose release was associated with greater coupled respiration and respiratory control (P < 0.05; n = 42, obs = 73), independent of age, sepsis, full-thickness burn size, and time postinjury testing. Coupled respiration was positively associated with VO2peak after adjustment for age, full-thickness burn size, and time of exercise testing (P < 0.025; n = 18, obs = 25). Conclusions: Burn severity, sex, and sepsis influence skeletal muscle mitochondrial function in burned children. Glucose control and functional capacity are associated with altered mitochondrial respiratory function in muscle of burn survivors, highlighting the relationship of altered muscle bioenergetics with the clinical sequelae accompanying severe burn trauma.