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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | E436-E448 |
| Journal | American Journal of Physiology - Endocrinology and Metabolism |
| Volume | 311 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 1 2016 |
Fingerprint
Keywords
- Burn injury
- Cachexia
- Hypermetabolism-induced oxidative stress
- Mitochondria proteases
- Mitochondrial unfolded protein response
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Physiology
- Medicine(all)
- Physiology (medical)
Cite this
Hypermetabolism and hypercatabolism of skeletal muscle accompany mitochondrial stress following severe burn trauma. / Ogunbileje, John; Porter, Craig; Herndon, David; Chao, Tony; Abdelrahman, Doaa R.; Papadimitriou, Anastasia; Chondronikola, Maria; Zimmers, Teresa A.; Reidy, Paul T.; Rasmussen, Blake; Sidossis, Labros S.
In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 311, No. 2, 01.08.2016, p. E436-E448.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Hypermetabolism and hypercatabolism of skeletal muscle accompany mitochondrial stress following severe burn trauma
AU - Ogunbileje, John
AU - Porter, Craig
AU - Herndon, David
AU - Chao, Tony
AU - Abdelrahman, Doaa R.
AU - Papadimitriou, Anastasia
AU - Chondronikola, Maria
AU - Zimmers, Teresa A.
AU - Reidy, Paul T.
AU - Rasmussen, Blake
AU - Sidossis, Labros S.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
KW - Burn injury
KW - Cachexia
KW - Hypermetabolism-induced oxidative stress
KW - Mitochondria proteases
KW - Mitochondrial unfolded protein response
UR - http://www.scopus.com/inward/record.url?scp=84983802020&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84983802020&partnerID=8YFLogxK
U2 - 10.1152/ajpendo.00535.2015
DO - 10.1152/ajpendo.00535.2015
M3 - Article
C2 - 27382037
AN - SCOPUS:84983802020
VL - 311
SP - E436-E448
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
SN - 0193-1849
IS - 2
ER -