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

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

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

In addition to skeletal muscle dysfunction, cancer cachexia is a systemic disease involving remodeling of non-muscle 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 OXPHOS coupling efficiency) was low in WAT during the induction of cachexia, due to high non-phosphorylating LEAK respiration. Liver RCR was low in C26 weight-stable and moderately cachexic mice due to 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

Sex-specific effects of maternal and postweaning high-fat diet on skeletal muscle mitochondrial respiration

Exposure to maternal over-nutrition in utero is linked with developmental programming of obesity, metabolic syndrome and cardiovascular disease in offspring, which may be exacerbated by postnatal high-fat (HF) diet. Skeletal muscle mitochondrial function contributes to substrate metabolism and is impaired in metabolic disease. We examined muscle mitochondrial respiration in male and female mice exposed to maternal HF diet in utero, followed by postweaning HF diet until middle age. After in utero exposure to maternal control (Con) or HF diet (45% kcal fat; 39.4% lard, 5.5% soybean oil), offspring were weaned to Con or HF, creating four groups: Con/Con (male/female (m/f), n=8/8), Con/HF (m/f, n=7/4), HF/Con (m/f, n=9/6) and HF/HF (m/f, n=4/4). Oxidative phosphorylation (OXPHOS) and electron transfer system (ETS) capacity were measured in permeabilized gastrocnemius bundles. Maternal HF diet increased fasting glucose and lean body mass in males and body fat percentage in both sexes (P⩽0.05). Maximal adenosine diphosphate-stimulated respiration (complex I OXPHOS) was decreased by maternal HF diet in female offspring (−21%, P=0.053), but not in male (−0%, P>0.05). Sexually divergent responses were exacerbated in offspring weaned to HF diet. In females, OXPHOS capacity was lower (−28%, P=0.041) when weaned to high-fat (HF/HF) v. control diet (HF/Con). In males, OXPHOS (+33%, P=0.009) and ETS (+42%, P=0.016) capacity increased. Our data suggest that maternal lard-based HF diet, rich in saturated fat, affects offspring skeletal muscle respiration in a sex-dependent manner, and these differences are exacerbated by HF diet in adulthood

Effect of knee and trunk angle on kinetic variables during the isometric mid-thigh pull : test-retest reliability

The isometric midthigh pull (IMTP) has been used to monitor changes in force, maximum rate of force development (mRFD), and impulse, with performance in this task being associated with performance in athletic tasks. Numerous postures have been adopted in the literature, which may affect the kinetic variables during the task; therefore, the aim of this investigation was to determine whether different knee-joint angles (120°, 130°, 140°, and 150°) and hip-joint angles (125° and 145°), including the subjects preferred posture, affect force, mRFD, and impulse during the IMTP. Intraclass correlation coefficients demonstrated high within-session reliability (r ≥ .870, P .819, P .05, Cohen d = 0.037, power = .408), mRFD (P > .05, Cohen d = 0.037, power = .409), or impulse at 100 ms (P > .05, Cohen d = 0.056, power = .609), 200 ms (P > .05, Cohen d = 0.057, power = .624), or 300 ms (P > .05, Cohen d = 0.061, power = .656) across postures. Smallest detectable differences demonstrated that changes in performance of >1.3% in peak isometric force, >10.3% in mRFD, >5.3% in impulse at 100 ms, >4.4% in impulse at 200 ms, and >7.1% in impulse at 300 ms should be considered meaningful, irrespective of posture

Respiration mitochondriale, données de base

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Weightlifting pulling derivatives : Rationale for implementation and application

This review article examines previous weightlifting literature and provides a rationale for the use of weightlifting pulling derivatives that eliminate the catch phase for athletes who are not competitive weightlifters. Practitioners should emphasize the completion of the triple extension movement during the second pull phase that is characteristic of weightlifting movements as this is likely to have the greatest transference to athletic performance that is dependent on hip, knee, and ankle extension. The clean pull, snatch pull, hang high pull, jump shrug, and mid-thigh pull are weightlifting pulling derivatives that can be used in the teaching progression of the full weightlifting movements and are thus less complex with regard to exercise technique. Previous literature suggests that the clean pull, snatch pull, hang high pull, jump shrug, and mid-thigh pull may provide a training stimulus that is as good as, if not better than, weightlifting movements that include the catch phase. Weightlifting pulling derivatives can be implemented throughout the training year, but an emphasis and de-emphasis should be used in order to meet the goals of particular training phases. When implementing weightlifting pulling derivatives, athletes must make a maximum effort, understand that pulling derivatives can be used for both technique work and building strength–power characteristics, and be coached with proper exercise technique. Future research should consider examining the effect of various loads on kinetic and kinematic characteristics of weightlifting pulling derivatives, training with full weightlifting movements as compared to training with weightlifting pulling derivatives, and how kinetic and kinematic variables vary between derivatives of the snatch