Journal Club Article Summaries

Overview
 Mitochondrial respiration = series of reactions that breakdown substrates (fat/CHO) to create ATP
 Oxidative phosphorylation = creation of ADPATP via ATP synthase + oxygen as final electron
acceptor
 Stress induced hypermetabolism can last 1-2 year post-burn – increased long-term
cachexia/morbidity
 Increased ATP consuming reactions = ~55-60% hyper metabolic response to meet energy demand1
o Protein synthesis (~20%)
o Hepatic gluconeogenesis (~10%)
o Glucose/fatty acid breakdown (~10%)
 Does not explain entirety of hypermetabolic response and total O2 consumption by body.
 Uncoupled vs. Coupled skeletal muscle mitochondria function
o Coupled
 Coupled reaction energy required by 1 process is supplied by another process.
 80% of mitochondrial respiration is coupled to ADP phosphorylation in healthy humans1.
Remainder attributable to proton leaks (i.e., heat production)1.
o Uncoupled
 Proton (H+) gradient becomes dysfunctional/out of equilibrium
 UCP proteins produce heat (skin barrier compromised)

Uncoupled skeletal muscle mitochondria contribute to hyper metabolism in severely burned adults
(2014)
Purpose
 Does skeletal muscle mitochondria function change during severe burns – if so, does it favor
thermogenesis.
Participants
 Severely burned male adults (n=6); 68±19% TBSA (>40% was minimum) - mostly full thickness
 Healthy adult males controls (n=12)
 DEXA  Body composition/body mass not significantly different between controls vs. pts
Methods
 All received standard burn care – fluid resuscitation, debridement, wound dressings, grafting etc.
 All fed same EN formula – 1,500 kcal/m2 body area + 1,500 kcal/m2 burn area via NGT
 Muscle biopsies (vastus lateralis) & Indirect Calorimetry
o Collected 2 different days @ ~1wk and ~3wk post injury
 11±5 and 21±8 days (biopsy)
 IC attempted on biopsy days, but not able to perform every time. Unable to perform on 1 pt
(1 wk interval) and another at 3 wk interval.
o REE – IC measurement compared to Harris Benedict (standard method)
Findings
 IC sig. higher vs. predicted REE at both time points (~850 kcals, ~40% higher)
 Burn pts had lower mitochondrial density vs. controls at both time points (citrate synthase)
 Non-normalized for mitochondrial density:
o Coupled mitochondrial respiration lower in burn pts vs. controls likely due to reduced
mitochondrial density within the muscle.
o No difference in uncoupling seen burn vs. control
 Normalized for mitochondrial density (via citrate synthase activity)
o Burn had higher levels coupled and uncoupled mitochondrial respiration
o Burn compensatory effect; remaining functional mito. = inc respiratory capacity per mito
o However  burn group had higher amount of mitochondrial uncoupling  less efficient ATP
production (H+ leaked across membrane = lost as heat)
 % mitochondrial oxygen consumption
  Control – 69% (phosphorylation) | 31% (thermogenesis)
 1 wk – 32% (phosphorylation) | 68% (thermogenesis)
 3 wk – 36% (phosphorylation) | 64% (thermogenesis)
Conclusions
 Skeletal muscle mitochondria in severe burn victims have greater mitochondrial uncoupling
therefore are more thermogenic vs. ATP producing = energy dissipated as heat
o Limits mitochondria ability to produce ATP
o However…these were measurements of maximal mito respiration = not normal
 Is this a bad adaptation? ….not necessarily.
o Good - loss of skin barrier = lose heat easily. Heat generation = keep body thermoneutral.
o Bad? - at the expense of body energy stores (fat/CHO)  energy needs to create heat 
elevated metabolic rate (hypermetabolism)
 Proposed molecular explanations for increased proton leak (heat production)
o Reduced genetic transcripts involved in oxidative phosphorylation?
o Increased expression uncoupling protein (UCP) in mitochondrial membrane?
o Mechanism for other patient populations under physiology stress (sepsis, cancer etc.)?
Limitations
 Muscle biopsy collection days not standardized (large variability), low sample size

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

severely burned children (2016)

Purpose
 Determine if acute changes in mitochondrial function last long-term (~2 yrs post-hospitalization)
along with known long-term hypermetabolic response (up to 2 years)
o Previous study only looked at ~3 wks post
Participants
 Control – healthy males (n=16) | 22-30 yrs (***ethical constraints to having children as controls)
 Burn – children (n = 69) | 77% male, 23% female | 3-13 yrs | 44±12% TBSA >30% TBSA burn
Methods (same as previous study for most part)
 All received standard burn care – fluid resuscitation, excision, wound dressings, grafting etc.
 All fed same EN formula – 1,500 kcal/m2 body area + 1,500 kcal/m2 burn area via NGT
 Muscle biopsy (vastus lateralis) & Indirect Calorimetry
o Both done at: 2 weeks (n=18), 2 weeks (n=18), 6 months (n=18), 12 months (n=25) and 24
months (n=18) post-burn
o REE – IC measurement compared to Harris Benedict (standard method)
 Mitochondrial function done via tissue
 Respiratory Control Ratio (RCR) = measure mitochondrial coupling control (lower = less coupling, less
ability of mito to make ATP)
 Substrate Control Ratio (SCR) = measure mitochondrial electron transfer function
 Coupling Control Ratio (CCR) = ADPATP phosphorylation measure (sensitive to oligomycin)
 1-CCR = Coupling Control Factor (CCF) = thermogenesis measure (insensitive to oligomycin, proton shifts
independent of ATP synthase pumping action = heat generation)
 Fraction Control Ratio (FCR) = determines % of phosphorylation vs. thermogenesis in setting of maximal
respiration
Findings
 Hypermetabolism highest at 2-wk interval
 (RCR) Mitochondrial ATP production is reduced post-burn – recovers around ~6 mo
 (SCR) Mitochondrial sensitivity to substrates is reduced post-burn – recovers around ~6 mo
 (CCR:CCF ratio) reduced coupling control and higher thermogenesis up to 2 years post burn
 Reduced SKM mitochondrial coupling control associated with hypermetabolism
Conclusions
 Limited ATP producing capacity not a concern in vivo since mitochondria only max out during intense
muscular contractions (i.e. high intensity exercise, pts = immobile/at rest). ATP supply likely meets
demand.
 Mitochondria exhibit thermogenic response up to 2 yrs post burn and this alteration in mitochondria
function is associated with elevated REE/hypermetabolic response in burns
o Recovery could be blunted; especially growth in children which is great concern given children are
in rapid state of growth
o Improvement in mitochondrial coupling control seen ~6 mo
Limitations
 Controls = all male adults; Burn = male and females + children
 Corrected for mitochondrial density like previous study? Or couldn’t bc can’t have child controls

Overall
 Suggests poor mitochondrial coupling control in skeletal muscle post-burn (adults/children)
 Suggests mitochondria become more thermogenic in nature which contributes to prolonged
hypermetabolism up to 2 years post-burn
 Uncoupling protein 2 (UCP2) expression elevated post-burn in mitochondrial membrane may
account for increased “leakness” to H+  heat production?????

References
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753602/
2018 – Role of Mitochondrial Stress in Muscle Wasting Following Severe Burn Trauma (LATEST
SUMMARY)

Proposed Mechanism Mitochondrial-induced Muscle Wasting

 Severe burns = O2 consumption (150%)
  hyper metabolism   electron transfer byproducts (ROS)
 ROS (within mitochondria  transfer to outside into cell)
o protein unfolding/oxidation (mitochondrial + in cell)
o proteasomes (clean out proteins)
 mitochondrial (and cell?) protein turnover
o AA’s diverted form SKM to mitochondria and intracellular space to repair
 mitochondrial membrane protein expression that transfer proteins into
mito
o Mitochondria are critical organelles (ATP production)
 ROS doesn’t survive physiological purpose vs. increased thermogenesis (help keep
temp normal w/ missing skin barrier)
 Leads to SKM wasting???

Therapeutic Strategies
 Antioxidants that can cross into the mitochondrial membrane (marine invertebrates? ostrich eggs?)
The Role of Mitochondrial Stress in Muscle Wasting Following Severe Burn Trauma (2018)
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