scholarly journals Tissue-specific dysregulation of mitochondrial respiratory capacity and coupling control in colon-26 tumor-induced cachexia

2019 ◽  
Vol 317 (1) ◽  
pp. R68-R82 ◽  
Author(s):  
Jessica L. Halle ◽  
Gabriel S. Pena ◽  
Hector G. Paez ◽  
Adrianna J. Castro ◽  
Harry B. Rossiter ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Mitochondrial Function ◽  
Cancer Cachexia ◽  
Systemic Disease ◽  
Respiratory Capacity ◽  
Tissue Specific ◽  
Colon 26 ◽  
Specific Control ◽  
Mitochondrial Respiratory

In addition to skeletal muscle dysfunction, cancer cachexia is a systemic disease involving remodeling of nonmuscle organs such as adipose and liver. Impairment of mitochondrial function is associated with multiple chronic diseases. The tissue-specific control of mitochondrial function in cancer cachexia is not well defined. This study determined mitochondrial respiratory capacity and coupling control of skeletal muscle, white adipose tissue (WAT), and liver in colon-26 (C26) tumor-induced cachexia. Tissues were collected from PBS-injected weight-stable mice, C26 weight-stable mice and C26 mice with moderate (10% weight loss) and severe cachexia (20% weight loss). The respiratory control ratio [(RCR) an index of oxidative phosphorylation (OXPHOS) coupling efficiency] was low in WAT during the induction of cachexia because of high nonphosphorylating LEAK respiration. Liver RCR was low in C26 weight-stable and moderately cachexic mice because of reduced OXPHOS. Liver RCR was further reduced with severe cachexia, where Ant2 but not Ucp2 expression was increased. Ant2 was inversely correlated with RCR in the liver ( r = −0.547, P < 0.01). Liver cardiolipin increased in moderate and severe cachexia, suggesting this early event may also contribute to mitochondrial uncoupling. Impaired skeletal muscle mitochondrial respiration occurred predominantly in severe cachexia, at complex I. These findings suggest that mitochondrial function is subject to tissue-specific control during cancer cachexia, whereby remodeling in WAT and liver arise early and may contribute to altered energy balance, followed by impaired skeletal muscle respiration. We highlight an under-recognized role of liver and WAT mitochondrial function in cancer cachexia and suggest mitochondrial function of multiple tissues to be therapeutic targets.

scholarly journals Tissue-specific dysregulation of mitochondrial respiratory capacity and coupling control in colon-26 tumor-induced cachexia

2018 ◽  
Author(s):  
Andy V Khamoui ◽  
Jessica L Halle ◽  
Gabriel S Pena ◽  
Hector G Paez ◽  
Harry B Rossiter ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Mitochondrial Function ◽  
Cancer Cachexia ◽  
Systemic Disease ◽  
Respiratory Capacity ◽  
Tissue Specific ◽  
Colon 26 ◽  
Specific Control ◽  
Mitochondrial Respiratory

In addition to skeletal muscle dysfunction, recent frameworks describe cancer cachexia as a systemic disease involving remodeling of non-muscle organs such as adipose and liver. Impairment of mitochondrial function is associated with multiple diseases. The tissue-specific control of mitochondrial function in cancer cachexia is not well-defined. This study determined mitochondrial respiratory capacity and coupling control of skeletal muscle, white adipose tissue (WAT), and liver in colon-26 (C26) tumor-induced cachexia. Tissues were collected from PBS-injected weight-stable mice, C26 mice that were weight-stable, and C26 mice with moderate (10% weight loss) and severe cachexia (20% weight loss). WAT showed high non-phosphorylating LEAK respiration and reduced respiratory control ratio (RCR, index of OXPHOS coupling efficiency) during the induction of cachexia. Liver RCR decreased early due to cancer, and further declined with severe cachexia, where Ant2 but not Ucp2 expression was increased. Ant2 also related inversely with RCR in the liver (r=-0.547, p<0.01), suggesting a role for Ant2 in uncoupling of liver OXPHOS. Increased liver cardiolipin occurred during moderate cachexia and remained elevated in severe cachexia, suggesting this early event may also contribute to uncoupling. Impaired skeletal muscle mitochondrial respiration occurred predominantly in severe cachexia. These findings suggest that mitochondrial function is subject to tissue-specific control during cancer cachexia, whereby remodeling in WAT and liver arise early and could contribute to altered energy balance, followed by impaired skeletal muscle respiration. We highlight an underrecognized role of liver mitochondria in cancer cachexia, and suggest mitochondrial function of multiple tissues to be targets for therapeutic intervention.

scholarly journals Atorvastatin impairs liver mitochondrial function in obese Göttingen Minipigs but heart and skeletal muscle are not affected

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Liselotte Bruun Christiansen ◽  
Tine Lovsø Dohlmann ◽  
Trine Pagh Ludvigsen ◽  
Ewa Parfieniuk ◽  
Michal Ciborowski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Citrate Synthase ◽  
Obese Group ◽  
Control Group ◽  
Dependent Manner ◽  
Respiratory Capacity ◽  
Protein Carbonyl Content ◽  
Functional Changes ◽  
Mitochondrial Respiratory

AbstractStatins lower the risk of cardiovascular events but have been associated with mitochondrial functional changes in a tissue-dependent manner. We investigated tissue-specific modifications of mitochondrial function in liver, heart and skeletal muscle mediated by chronic statin therapy in a Göttingen Minipig model. We hypothesized that statins enhance the mitochondrial function in heart but impair skeletal muscle and liver mitochondria. Mitochondrial respiratory capacities, citrate synthase activity, coenzyme Q10 concentrations and protein carbonyl content (PCC) were analyzed in samples of liver, heart and skeletal muscle from three groups of Göttingen Minipigs: a lean control group (CON, n = 6), an obese group (HFD, n = 7) and an obese group treated with atorvastatin for 28 weeks (HFD + ATO, n = 7). Atorvastatin concentrations were analyzed in each of the three tissues and in plasma from the Göttingen Minipigs. In treated minipigs, atorvastatin was detected in the liver and in plasma. A significant reduction in complex I + II-supported mitochondrial respiratory capacity was seen in liver of HFD + ATO compared to HFD (P = 0.022). Opposite directed but insignificant modifications of mitochondrial respiratory capacity were seen in heart versus skeletal muscle in HFD + ATO compared to the HFD group. In heart muscle, the HFD + ATO had significantly higher PCC compared to the HFD group (P = 0.0323). In the HFD group relative to CON, liver mitochondrial respiration decreased whereas in skeletal muscle, respiration increased but these changes were insignificant when normalizing for mitochondrial content. Oral atorvastatin treatment in Göttingen Minipigs is associated with a reduced mitochondrial respiratory capacity in the liver that may be linked to increased content of atorvastatin in this organ.

Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

2012 ◽  
Vol 302 (6) ◽  
pp. E731-E739 ◽  
Author(s):  
Maria H. Holmström ◽  
Eduardo Iglesias-Gutierrez ◽  
Juleen R. Zierath ◽  
Pablo M. Garcia-Roves
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Respiration ◽  
Mitochondrial Dynamics ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Respiratory Capacity ◽  
Tissue Specific ◽  
Mitochondrial Respiratory

The tissue-specific role of mitochondrial respiratory capacity in the development of insulin resistance and type 2 diabetes is unclear. We determined mitochondrial function in glycolytic and oxidative skeletal muscle and liver from lean (+/ ?) and obese diabetic ( db/db) mice. In lean mice, the mitochondrial respiration pattern differed between tissues. Tissue-specific mitochondrial profiles were then compared between lean and db/db mice. In liver, mitochondrial respiratory capacity and protein expression, including peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), was decreased in db/db mice, consistent with increased mitochondrial fission. In glycolytic muscle, mitochondrial respiration, as well as protein and mRNA expression of mitochondrial markers, was increased in db/db mice, suggesting increased mitochondrial content and fatty acid oxidation capacity. In oxidative muscle, mitochondrial complex I function and PGC-1α and mitochondrial transcription factor A (TFAM) protein levels were decreased in db/db mice, along with increased level of proteins related to mitochondrial dynamics. In conclusion, mitochondrial respiratory performance is under the control of tissue-specific mechanisms and is not uniformly altered in response to obesity. Furthermore, insulin resistance in glycolytic skeletal muscle can be maintained by a mechanism independent of mitochondrial dysfunction. Conversely, insulin resistance in liver and oxidative skeletal muscle from db/db mice is coincident with mitochondrial dysfunction.

scholarly journals Mitochondrial Respiratory Capacity and Coupling Control of Skeletal Muscle in Colon-26 Tumor-Induced Cachexia

2018 ◽  
Vol 50 (5S) ◽  
pp. 197
Author(s):  
Jessica L. Halle ◽  
Gabriel S. Pena ◽  
Hector G. Paez ◽  
Joseph P. Carzoli ◽  
Michael C. Zourdos ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Respiratory Capacity ◽  
Colon 26 ◽  
Mitochondrial Respiratory

scholarly journals Colon 26 adenocarcinoma (C26)-induced cancer cachexia impairs skeletal muscle mitochondrial function and content

2019 ◽  
Vol 40 (1) ◽  
pp. 59-65 ◽  
Author(s):  
Daria Neyroud ◽  
Rachel L. Nosacka ◽  
Andrew R. Judge ◽  
Russell T. Hepple
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Cancer Cachexia ◽  
Colon 26

scholarly journals Hepatic proteome analysis reveals altered mitochondrial metabolism and suppressed acyl-CoA synthetase-1 in colon-26 tumor-induced cachexia

2020 ◽  
Vol 52 (5) ◽  
pp. 203-216 ◽  
Author(s):  
Andy V. Khamoui ◽  
Dorota Tokmina-Roszyk ◽  
Harry B. Rossiter ◽  
Gregg B. Fields ◽  
Nishant P. Visavadiya
Keyword(s):  
Weight Loss ◽  
Cancer Cachexia ◽  
Systemic Disease ◽  
Coupling Efficiency ◽  
Proteome Analysis ◽  
Colon 26 ◽  
Cellular Processes ◽  
Linear Relationships ◽  
Life Threatening ◽  
A Chain

Cachexia is a life-threatening complication of cancer traditionally characterized by weight loss and muscle dysfunction. Cachexia, however, is a systemic disease that also involves remodeling of nonmuscle organs. The liver exerts major control over systemic metabolism, yet its role in cancer cachexia is not well understood. To advance the understanding of how the liver contributes to cancer cachexia, we used quantitative proteomics and bioinformatics to identify hepatic pathways and cellular processes dysregulated in mice with moderate and severe colon-26 tumor-induced cachexia; ~300 differentially expressed proteins identified during the induction of moderate cachexia were also differentially regulated in the transition to severe cachexia. KEGG pathway enrichment revealed representation by oxidative phosphorylation, indicating altered hepatic mitochondrial function as a common feature across cachexia severity. Glycogen catabolism was also observed in cachexic livers along with decreased pyruvate dehydrogenase protein X component (Pdhx), increased lactate dehydrogenase A chain (Ldha), and increased lactate transporter Mct1. Together this suggests altered lactate metabolism and transport in cachexic livers, which may contribute to energetically inefficient interorgan lactate cycling. Acyl-CoA synthetase-1 (ACSL1), known for activating long-chain fatty acids, was decreased in moderate and severe cachexia based on LC-MS/MS analysis and immunoblotting. ACSL1 showed strong linear relationships with percent body weight change and muscle fiber size (R2 = 0.73–0.76, P < 0.01). Mitochondrial coupling efficiency, which is compromised in cachexic livers to potentially increase energy expenditure and weight loss, also showed a linear relationship with ACSL1. Findings suggest altered mitochondrial and substrate metabolism of the liver in cancer cachexia, and possible hepatic targets for intervention.

High aerobic exercise capacity predicts increased mitochondrial response to exercise training

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Schwarzer ◽  
S Zeeb ◽  
E Heyne ◽  
L.G Koch ◽  
S.L Britton ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Exercise Training ◽  
Aerobic Exercise ◽  
Exercise Capacity ◽  
Mitochondrial Function ◽  
Citrate Synthase ◽  
Respiratory Capacity ◽  
The Impact ◽  
Mitochondrial Respiratory

Abstract   Low exercise capacity is a strong predictor of all-cause cardiovascular mortality and morbidity. In contrast, high exercise capacity is protective and “physical fitness” is considered beneficial. These effects seem to be mediated through mitochondrial function. Importantly, exercise capacity consists of an intrinsic (genetic) and an extrinsic (exercise, environmental) part. In humans, these two parts cannot be truly separated. The rat model of high (HCR) and low (LCR) capacity runners allows to distinguish between the two parts. We assessed mitochondrial function in this model, specifically investigating the impact of exercise training on mitochondrial respiratory capacity. HCR and LCR were divided into control and exercised groups. Exercise capacity was determined individually using a ramped test. Animals were trained five times a week for four weeks on a treadmill. Mitochondria were isolated from heart, M. gastrocnemius and liver. Citrate synthase activity and protein content were determined photometrically and respiratory capacity was measured using a Clark-type electrode. At the same age and tibia length, LCR-C were heavier and had a lower heart to body weight ratio than HCR-C. Citrate synthase activity was lower in skeletal muscle of LCR but cardiac citrate synthase was not different between sedentary HCR and LCR. Respiratory capacity in heart and liver was not different between sedentary HCR and LCR but was lower in skeletal muscle in LCR compared to HCR with all selected substrates (glutamate: 86,0±17,6 vs. 63,7±8,0; succinate: 203±19 vs. 136±17 nAO/min/mg Protein). Exercise training led to an increase in body weight in HCR but did not change body weight in LCR. Similarly, gastrocnemius and soleus weights only increased with exercise in HCR. Exercise led to an increase in citrate synthase activity in hearts of HCR (0,78±0,07 vs. 1,58±0,45 U/mg Protein) but not of LCR. Consistently, mitochondrial respiratory capacity was found increased in HCR with exercise in heart with all substrates (glutamate: 261±43 vs. 305±35; succinate 417±32 vs. 539±65 nAO/min/mg Protein). Liver was not affected by exercise. Conclusion Our data suggest that genetic predisposition for aerobic capacity additionally affects the response of mitochondria to exercise. Thus, it may be possible that the “born runner” benefits more from aerobic exercise training than the “less genetically equipped counterpart”. Funding Acknowledgement Type of funding source: None

Leucine augments specific skeletal muscle mitochondrial respiratory pathways during recovery following 7 days of physical inactivity in older adults

2021 ◽  
Author(s):  
Emily J. Arentson-Lantz ◽  
Jasmine Mikovic ◽  
Nisha Bhattarai ◽  
Christopher S. Fry ◽  
Séverine Lamon ◽  
...  
Keyword(s):  
Older Adults ◽  
Skeletal Muscle ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Bed Rest ◽  
Metabolic Clearance ◽  
Leucine Supplementation ◽  
Respiratory Capacity ◽  
Antioxidant Defense Systems ◽  
Mitochondrial Respiratory

Leucine supplementation attenuates the loss of skeletal muscle mass and function in older adults during bed rest. We sought to determine if leucine could also preserve and/or restore mitochondrial function and muscle oxidative capacity during periods of disuse and rehabilitation. Healthy older adults (69.1 ± 1.1 years) consumed a structured diet with supplemental leucine (LEU: 0.06 g/ kg body weight/ meal; n=8) or alanine (CON: 0.06 g/ kg body weight/meal; n=8) during 7 days of bed rest and 5 days of inpatient rehabilitation. A 75 g oral glucose tolerance test was performed at baseline (PreBR), after bed rest (PostBR) and rehabilitation (PostRehab) and used to calculate an indicator of insulin sensitivity, metabolic clearance rate. (MCR). Tissue samples from the m. vastus lateralis were collected PreBR, PostBR, and PostRehab to assess mitochondrial respiratory capacity and protein markers of the oxidative phosphorylation and a marker of the antioxidant defense systems. During bed rest, leucine tended to preserve insulin sensitivity (Change in MCR, CON vs. LEU: -3.5 ± 0.82 vs LEU: -0.98 ± 0.88, p=0.054), but had no effect on mitochondrial respiratory capacity (Change in State 3+succinate CON vs. LEU -8.7 ± 6.1 vs. 7.3 ± 4.1 pmol O2/sec/mg tissue, p=0.10) Following rehabilitation, leucine increased ATP-linked respiration (CON vs. LEU: -8.9 ± 6.2 vs. 15.5± 4.4 pmol O2/sec/mg tissue, p=0.0042). While the expression of mitochondrial respiratory and antioxidant proteins was not impacted, leucine supplementation preserved specific pathways of mitochondrial respiration, insulin sensitivity and a marker of oxidative stress during bed rest and rehabilitation.

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