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Typical vivarium temperatures (20-26°C) induce facultative thermogenesis in mice, a process attributable in part to uncoupling protein-1 (UCP1). The impact of modest changes in housing temperature on whole body and adipose tissue energetics in mice remains unclear. Here, we determined the effects of transitioning mice from 24°C to 30° C on total energy expenditure and adipose tissue protein signatures. C57BL/6J mice were housed at 24°C for 2 wk and then either remained at 2°C (n = 16/group, 8M/8F) or were transitioned to 30°C (n = 16/group, 8M/8F) for 4 wk. Total energy expenditure and its components were determined by indirect calorimetry. Interscapular brown adipose tissue (iBAT) and inguinal white adipose tissue (iWAT) proteins were quantified by Western blot and quantitative proteomics. Transitioning from 24°C to 30°C reduced total energy expenditure in both male (-25%) and female (-16%) mice, which was attributable to lower basal energy expenditure in males (-36%) and females (-40%). Total iBAT UCP1 protein content was 50% lower at 30°C compared with 24°C, whereas iWAT UCP1 protein content was similar between conditions. iBAT UCP1 protein content remained 20-fold greater than iWAT at 30°C. In iBAT and iWAT, 183 and 41 proteins were differentially expressed between 24°C and 30°C, respectively. iWAT proteins (257) differentially expressed between sexes at 30°C were not differentially expressed at 24°C. Thus, 30°C housing lowers total energy expenditure of mice when compared with an ambient temperature (24°C) that falls within the National Research Council's guidelines for housing laboratory mice. Lower iBAT UCP1 content accompanied chronic housing at 30°C. Furthermore, housing temperature influences sexual dimorphism in the iWAT proteome. These data have implications regarding the optimization of preclinical models of human disease. [ABSTRACT FROM AUTHOR]

The contribution of myofibrillar protein synthesis (MyoPS) to recovery from skeletal muscle damage in humans is unknown. Recreationally active men and women consumed a daily protein-polyphenol beverage targeted at increasing amino acid availability and reducing inflammation (PPB; n = 9), both known to affect MyoPS, or an isocaloric placebo (PLA; n = 9) during 168 h of recovery from 300 maximal unilateral eccentric contractions (EE). Muscle function was assessed daily. Muscle biopsies were collected for 24, 27, 36, 72, and 168 h for MyoPS measurements using ²H2O and expression of 224 genes using RT-qPCR and pathway analysis. PPB improved recovery of muscle function, which was impaired for 5 days after EE in PLA (interaction P < 0.05). Acute postprandial MyoPS rates were unaffected by nutritional intervention (24--27 h). EE increased overnight (27--36 h) MyoPS versus the control leg (PLA: 33 ± 19%; PPB: 79 ± 25%; leg P < 0.01), and PPB tended to increase this further (interaction P = 0.06). Daily MyoPS rates were greater with PPB between 72 and 168 h after EE, albeit after function had recovered. Inflammatory and regenerative signaling pathways were dramatically upregulated and clustered after EE but were unaffected by nutritional intervention. These results suggest that accelerated recovery from EE is not explained by elevated MyoPS or suppression of inflammation. [ABSTRACT FROM AUTHOR]

Severely burned children experience a chronic state of sympathetic nervous system activation that is associated with hypermetabolic/cardiac stress and muscle wasting. Metformin, a diabetes medication, helps control hyperglycemia in obese diabetic populations, and exercise has been shown to improve exercise strength and aerobic exercise capacity after severe burns. However, whether exercise improves glycemic control in burned children and whether combining exercise and metformin improves outcomes to a greater degree than exercise alone are unknown. We tested the hypothesis that a 6-wk exercise program combined with short-term metformin administration (E + M) improves aerobic and strength exercise capacity to a greater degree than exercise and placebo (E), while improving glucose tolerance and muscle metabolic function. We found that, before exercise training, the metformin group compared with the placebo group had attenuated mitochondrial respiration (pmol·s−1·mg−1) for each state: state 2 (−22.5 ± 3), state 3 (−42.4 ± 13), and oxphos (−58.9 ± 19) (P ≤ 0.02, M vs. E + M group for each state). However, in the E + M group, exercise increased mitochondrial respiration in each state (P ≤ 0.05), with respiration being comparable to that in the E group (each P > 0.05). In both groups, exercise induced comparable improvements in strength (change from preexercise, Δ1.6 ± 0.6 N-M·kgLBM) and V̇o2peak (Δ9 ± 7 mlO2·kgLBM) as well as fasting glucose (Δ19.3 ± 13 mg·dl) and glucose AUC (Δ3402 ± 3674 mg·dl−1·min−1), as measured by a 75-g OGTT (all P ≤ 0.03). Exercise reduced resting energy expenditure in E + M (Δ539 ± 480 kcal/24 h, P < 0.01) but not E subjects (P = 0.68). Both groups exhibited reduced resting heart rate (Δ30 ± 23 beats/min, P ≤ 0.02). These data indicate that short-term metformin combined with exercise provides no further improvement beyond that of exercise alone for strength, exercise capacity, and glycemic control. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mitochondrial health is critical to physiological function, particularly in tissues with high ATP turnover, such as striated muscle. It has been postulated that derangements in skeletal muscle mitochondrial function contribute to impaired physical function in older adults. Here, we determined mitochondrial respiratory capacity and coupling control in skeletal muscle biopsies obtained from young and older adults. Twenty-four young (28 ± 7 yr) and thirty-one older (62 ± 8 yr) adults were studied. Mitochondrial respiration was determined in permeabilized myofibers from the vastus lateralis after the addition of substrates oligomycin and CCCP. Thereafter, mitochondrial coupling control was calculated. Maximal coupled respiration (respiration linked to ATP production) was lower in muscle from older vs. young subjects (P < 0.01), as was maximal uncoupled respiration (P = 0.06). Coupling control in response to the ATP synthase inhibitor oligomycin was lower in older adults (P < 0.05), as was the mitochondria flux control ratio, coupled respiration normalized to maximal uncoupled respiration (P < 0.05). Calculation of respiratory function revealed lower respiration linked to ATP production (P < 0.001) and greater reserve respiration (P < 0.01); i.e., respiratory capacity not used for phosphorylation in muscle from older adults. We conclude that skeletal muscle mitochondrial respiratory capacity and coupling control decline with age. Lower respiratory capacity and coupling efficiency result in a reduced capacity for ATP production in skeletal muscle of older adults. [ABSTRACT FROM AUTHOR]

Elevated metabolic rate is a hallmark of the stress response to severe burn injury. This response is mediated in part by adrenergic stress and is responsive to changes in ambient temperature. We hypothesize that uncoupling of oxidative phosphorylation in skeletal muscle mitochondria contributes to increased metabolic rate in burn survivors. Here, we determined skeletal muscle mitochondrial function in healthy and severely burned adults. Indirect calorimetry was used to estimate metabolic rate in burn patients. Quadriceps muscle biopsies were collected on two separate occasions (11 ± 5 and 21 ± 8 days postinjury) from six severely burned adults (68 ± 19% of total body surface area burned) and 12 healthy adults. Leak, coupled, and uncoupled mitochondrial respiration was determined in permeabilized myofiber bundles. Metabolic rate was significantly greater than predicted values for burn patients at both time points (P < 0.05). Skeletal muscle oxidative capacity, citrate synthase activity, a marker of mitochondrial abundance, and mitochondrial sensitivity to oligomycin were all lower in burn patients vs. controls at both time points (P < 0.05). A greater proportion of maximal mitochondrial respiration was linked to thermogenesis in burn patients compared with controls (P < 0.05). Increased metabolic rate in severely burned adults is accompanied by derangements in skeletal muscle mitochondrial function. Skeletal muscle mitochondria from burn victims are more uncoupled, indicating greater heat production within skeletal muscle. Our findings suggest that skeletal muscle mitochondrial dysfunction contributes to increased metabolic rate in burn victims. [ABSTRACT FROM AUTHOR]