scholarly journals The mechanisms of cachexia underlying muscle dysfunction in COPD

2013 ◽  
Vol 114 (9) ◽  
pp. 1253-1262 ◽  
Author(s):  
A. H. V. Remels ◽  
H. R. Gosker ◽  
R. C. J. Langen ◽  
A. M. W. J. Schols
Keyword(s):  
Oxidative Stress ◽  
Weight Loss ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Fiber Type ◽  
Oxidative Capacity ◽  
Diaphragm Muscle ◽  
Energy Deficit ◽  
Peripheral Muscle ◽  
Oxidative Phenotype

Pulmonary cachexia is a prevalent, debilitating, and well-recognized feature of COPD associated with increased mortality and loss of peripheral and respiratory muscle function. The exact cause and underlying mechanisms of cachexia in COPD are still poorly understood. Increasing evidence, however, shows that pathological changes in intracellular mechanisms of muscle mass maintenance (i.e., protein turnover and myonuclear turnover) are likely involved. Potential factors triggering alterations in these mechanisms in COPD include oxidative stress, myostatin, and inflammation. In addition to muscle wasting, peripheral muscle in COPD is characterized by a fiber-type shift toward a more type II, glycolytic phenotype and an impaired oxidative capacity (collectively referred to as an impaired oxidative phenotype). Atrophied diaphragm muscle in COPD, however, displays an enhanced oxidative phenotype. Interestingly, intrinsic abnormalities in (lower limb) peripheral muscle seem more pronounced in either cachectic patients or weight loss-susceptible emphysema patients, suggesting that muscle wasting and intrinsic changes in peripheral muscle's oxidative phenotype are somehow intertwined. In this manuscript, we will review alterations in mechanisms of muscle mass maintenance in COPD and discuss the involvement of oxidative stress, inflammation, and myostatin as potential triggers of cachexia. Moreover, we postulate that an impaired muscle oxidative phenotype in COPD can accelerate the process of cachexia, as it renders muscle in COPD less energy efficient, thereby contributing to an energy deficit and weight loss when not dietary compensated. Furthermore, loss of peripheral muscle oxidative phenotype may increase the muscle's susceptibility to inflammation- and oxidative stress-induced muscle damage and wasting.

scholarly journals Muscle oxidative capacity during IL-6-dependent cancer cachexia

2011 ◽  
Vol 300 (2) ◽  
pp. R201-R211 ◽  
Author(s):  
James P. White ◽  
Kristen A. Baltgalvis ◽  
Melissa J. Puppa ◽  
Shuichi Sato ◽  
John W. Baynes ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cytochrome C ◽  
Muscle Mass ◽  
Gastrocnemius Muscle ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Muscle Protein ◽  
Oxidative Capacity ◽  
Muscle Oxidative Capacity ◽  
Markers Of Oxidative Stress

Many diseases are associated with catabolic conditions that induce skeletal muscle wasting. These various catabolic states may have similar and distinct mechanisms for inducing muscle protein loss. Mechanisms related to muscle wasting may also be related to muscle metabolism since glycolytic muscle fibers have greater wasting susceptibility with several diseases. The purpose of this study was to determine the relationship between muscle oxidative capacity and muscle mass loss in red and white hindlimb muscles during cancer cachexia development in the Apc Min/+ mouse. Gastrocnemius and soleus muscles were excised from Apc Min/+ mice at 20 wk of age. The gastrocnemius muscle was partitioned into red and white portions. Body mass (−20%), gastrocnemius muscle mass (−41%), soleus muscle mass (−34%), and epididymal fat pad (−100%) were significantly reduced in severely cachectic mice ( n = 8) compared with mildly cachectic mice ( n = 6). Circulating IL-6 was fivefold higher in severely cachectic mice. Cachexia significantly reduced the mitochondrial DNA-to-nuclear DNA ratio in both red and white portions of the gastrocnemius. Cytochrome c and cytochrome- c oxidase complex subunit IV (Cox IV) protein were reduced in all three muscles with severe cachexia. Changes in muscle oxidative capacity were not associated with altered myosin heavy chain expression. PGC-1α expression was suppressed by cachexia in the red and white gastrocnemius and soleus muscles. Cachexia reduced Mfn1 and Mfn2 mRNA expression and markers of oxidative stress, while Fis1 mRNA was increased by cachexia in all muscle types. Muscle oxidative capacity, mitochondria dynamics, and markers of oxidative stress are reduced in both oxidative and glycolytic muscle with severe wasting that is associated with increased circulating IL-6 levels.

scholarly journals Continued Weight Loss and Sarcopenia Predict Poor Outcomes in Locally Advanced Pancreatic Cancer Treated with Chemoradiation

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 709 ◽  
Author(s):  
Patrick Naumann ◽  
Jonathan Eberlein ◽  
Benjamin Farnia ◽  
Thilo Hackert ◽  
Jürgen Debus ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Pancreatic Cancer ◽  
Weight Loss ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Statistical Tests ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Skeletal Muscle Index ◽  
Poor Outcomes

Background: Surgical resection offers the best chance of survival in patients with pancreatic cancer, but those with locally advanced disease (LAPC) are usually not surgical candidates. This cohort often receives either neoadjuvant chemotherapy or chemoradiation (CRT), but unintended weight loss coupled with muscle wasting (sarcopenia) can often be observed. Here, we report on the predictive value of changes in weight and muscle mass in 147 consecutive patients with LAPC treated with neoadjuvant CRT. Methods: Clinicopathologic data were obtained via a retrospective chart review. The abdominal skeletal muscle area (SMA) at the third lumbar vertebral body was determined via computer tomographic (CT) scans as a surrogate for the muscle mass and skeletal muscle index (SMI) calculated. Uni- and multi-variable statistical tests were performed to assess for impact on survival. Results: Weight loss (14.5 vs. 20.3 months; p = 0.04) and loss of muscle mass (15.1 vs. 22.2 months; p = 0.007) were associated with poor outcomes. The highest survival was observed in patients who had neither cachectic weight loss nor sarcopenia (27 months), with improved survival seen in those who ultimately received a resection (23 vs. 10 months; p < 0.001). Cox regression revealed that either continued weight loss or continued muscle wasting (SMA reduction) was predictive of poor outcomes, whereas a sarcopenic SMI was not. Conclusions: Loss of weight and lean muscle in patients with LAPC is prognostic when persistent. Therefore, both should be assessed longitudinally and considered before surgery.

scholarly journals Resistance training and timed essential amino acids protect against the loss of muscle mass and strength during 28 days of bed rest and energy deficit

2008 ◽  
Vol 105 (1) ◽  
pp. 241-248 ◽  
Author(s):  
Naomi Brooks ◽  
Gregory J. Cloutier ◽  
Samuel M. Cadena ◽  
Jennifer E. Layne ◽  
Carol A. Nelsen ◽  
...  
Keyword(s):  
Resistance Training ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Bed Rest ◽  
Essential Amino Acids ◽  
Energy Deficit ◽  
Active Recovery ◽  
Low Gravity ◽  
Muscle Area ◽  
Group 3

Spaceflight and bed rest (BR) result in losses of muscle mass and strength. Resistance training (RT) and amino acid (AA) supplementation are potential countermeasures to minimize these losses. However, it is unknown if timing of supplementation with exercise can optimize benefits, particularly with energy deficit. We examined the effect of these countermeasures on body composition, strength, and insulin levels in 31 men (ages 31–55 yr) during BR (28 days) followed by active recovery (14 days). Subjects were randomly assigned to essential AA supplementation (AA group, n = 7); RT with AA given 3 h after training (RT group, n = 12); or RT with AA given 5 min before training (AART group, n = 12). Energy intake was reduced by 8 ± 6%. Midthigh muscle area declined with BR for the AA > RT > AART groups: −11%, −3%, −4% ( P = 0.05). Similarly, greatest losses in lower body muscle strength were seen in the AA group (−22%). These were attenuated in the exercising groups [RT (−8%) and AART (−6%; P < 0.05)]. Fat mass and midthigh intramuscular fat increased after BR in the AA group (+3% and +14%, respectively), and decreased in the RT (−5% and −4%) and AART groups (−1 and −5%; P = 0.05). Muscle mass and strength returned toward baseline after recovery, but the AA group showed the lowest regains. Combined resistance training with AA supplementation pre- or postexercise attenuated the losses in muscle mass and strength by approximately two-thirds compared with AA supplement alone during BR and energy deficit. These data support the efficacy of combined AA and RT as a countermeasure against muscle wasting due to low gravity.

scholarly journals Loss of quadriceps muscle oxidative phenotype and decreased endurance in patients with mild-to-moderate COPD

2013 ◽  
Vol 114 (9) ◽  
pp. 1319-1328 ◽  
Author(s):  
Bram van den Borst ◽  
Ilse G. M. Slot ◽  
Valéry A. C. V. Hellwig ◽  
Bettine A. H. Vosse ◽  
Marco C. J. M. Kelders ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Skeletal Muscle ◽  
Fiber Type ◽  
Airflow Obstruction ◽  
Quadriceps Muscle ◽  
Activity Level ◽  
Load Test ◽  
Type I ◽  
Oxidative Phenotype

Being well-established in advanced chronic obstructive pulmonary disease (COPD), skeletal muscle dysfunction and its underlying pathology have been scarcely investigated in patients with mild-to-moderate airflow obstruction. We hypothesized that a loss of oxidative phenotype (oxphen) associated with decreased endurance is present in the skeletal muscle of patients with mild-to-moderate COPD. In quadriceps muscle biopsies from 29 patients with COPD (forced expiratory volume in 1 s [FEV1] 58 ± 16%pred, body mass index [BMI] 26 ± 4 kg/m2) and 15 controls (BMI 25 ± 3 kg/m2) we assessed fiber type distribution, fiber cross-sectional areas (CSA), oxidative and glycolytic gene expression, OXPHOS protein levels, metabolic enzyme activity, and levels of oxidative stress markers. Quadriceps function was assessed by isokinetic dynamometry, body composition by dual-energy X-ray absorptiometry, exercise capacity by an incremental load test, and physical activity level by accelerometry. Compared with controls, patients had comparable fat-free mass index, quadriceps strength, and fiber CSA, but quadriceps endurance was decreased by 29% ( P = 0.002). Patients with COPD had a clear loss of muscle oxphen: a fiber type I-to-II shift, decreased levels of OXPHOS complexes IV and V subunits (47% and 31%, respectively; P < 0.05), a decreased ratio of 3-hydroxyacyl-CoA dehydrogenase/phosphofructokinase (PFK) enzyme activities (38%, P < 0.05), and decreased peroxisome proliferator-activated receptor-γ coactivator-1α (40%; P < 0.001) vs. increased PFK (67%; P < 0.001) gene expression levels. Within the patient group, markers of oxphen were significantly positively correlated with quadriceps endurance and inversely with the increase in plasma lactate relative to work rate during the incremental test. Levels of protein carbonylation, tyrosine nitration, and malondialdehyde protein adducts were comparable between patients and controls. However, among patients, oxidative stress levels were significantly inversely correlated with markers of oxphen and quadriceps endurance. Reduced muscle endurance associated with underlying loss of muscle oxphen is already present in patients with mild-to-moderate COPD without muscle wasting.

scholarly journals Ubiquinol Reduces Muscle Wasting but Not Fatigue in Tumor-Bearing Mice

2014 ◽  
Vol 17 (3) ◽  
pp. 321-329 ◽  
Author(s):  
Yvonne Y. Clark ◽  
Loren E. Wold ◽  
Laura A. Szalacha ◽  
Donna O. McCarthy
Keyword(s):  
Oxidative Stress ◽  
Cardiac Function ◽  
Tumor Growth ◽  
Protein Degradation ◽  
Grip Strength ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Wheel Running ◽  
Behavioral Measures ◽  
Tumor Bearing

Purpose:Fatigue is the most common and distressing symptom reported by cancer patients during and after treatment. Tumor growth increases oxidative stress and cytokine production, which causes skeletal muscle wasting and cardiac dysfunction. The purpose of this study was to determine whether treatment with the antioxidant ubiquinol improves muscle mass, cardiac function, and behavioral measures of fatigue in tumor-bearing mice.Method:Adult female mice were inoculated with colon26 tumor cells. Half the control and tumor-bearing mice were administered ubiquinol (500 mg/kg/day) in their drinking water. Voluntary wheel running (i.e., voluntary running activity [VRA]) and grip strength were measured at Days 0, 8, 14, and 17 of tumor growth. Cardiac function was measured using echocardiography on Day 18 or 19. Biomarkers of inflammation, protein degradation, and oxidative stress were measured in serum and heart and gastrocnemius tissue.Results:VRA and grip strength progressively declined in tumor-bearing mice. Muscle mass and myocardial diastolic function were decreased, and expression of proinflammatory cytokines was increased in serum and muscle and heart tissue on Day 19 of tumor growth. Oxidative stress was present only in the heart, while biomarkers of protein degradation were increased only in the gastrocnemius muscle. Ubiquinol increased muscle mass in the tumor-bearing and control animals but had no effect on the expression of biomarkers of inflammation, protein degradation, or oxidative stress or on behavioral measures of fatigue.

scholarly journals Gsα deficiency in skeletal muscle leads to reduced muscle mass, fiber-type switching, and glucose intolerance without insulin resistance or deficiency

2009 ◽  
Vol 296 (4) ◽  
pp. C930-C940 ◽  
Author(s):  
Min Chen ◽  
Han-Zhong Feng ◽  
Divakar Gupta ◽  
James Kelleher ◽  
Kathryn E. Dickerson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Fiber Type ◽  
Oxidative Capacity ◽  
Whole Body ◽  
Kinetic Properties ◽  
Intracellular Camp ◽  
Type I ◽  
Muscle Adaptation ◽  
Α Subunit

The ubiquitously expressed G protein α-subunit Gsα is required for receptor-stimulated intracellular cAMP responses and is an important regulator of energy and glucose metabolism. We have generated skeletal muscle-specific Gsα-knockout (KO) mice (MGsKO) by mating Gsα-floxed mice with muscle creatine kinase-cre transgenic mice. MGsKO mice had normal body weight and composition, and their serum glucose, insulin, free fatty acid, and triglyceride levels were similar to that of controls. However, MGsKO mice were glucose intolerant despite the fact that insulin sensitivity and glucose-stimulated insulin secretion were normal, suggesting an insulin-independent mechanism. Isolated muscles from MGsKO mice had increased basal glucose uptake and normal responses to a stimulator of AMP-activated protein kinase (AMPK), which indicates that AMPK and its downstream pathways are intact. Compared with control mice, MGsKO mice had reduced muscle mass with decreased cross-sectional area and force production. In addition, adult MGsKO mice showed an increased proportion of type I (slow-twitch, oxidative) fibers based on kinetic properties and myosin heavy chain isoforms, despite the fact that these muscles had reduced expression of peroxisome proliferator-activated receptor coactivator protein-1α (PGC-1α) and reduced mitochondrial content and oxidative capacity. Therefore Gsα deficiency led to fast-to-slow fiber-type switching, which appeared to be dissociated from the expected change in oxidative capacity. MGsKO mice are a valuable model for future studies of the role of Gsα signaling pathways in skeletal muscle adaptation and their effects on whole body metabolism.

scholarly journals Aging reduces succinate dehydrogenase activity in rat type IIx/IIb diaphragm muscle fibers

2020 ◽  
Vol 128 (1) ◽  
pp. 70-77 ◽  
Author(s):  
Matthew J. Fogarty ◽  
Natalia Marin Mathieu ◽  
Carlos B. Mantilla ◽  
Gary C. Sieck
Keyword(s):  
Succinate Dehydrogenase ◽  
Dehydrogenase Activity ◽  
Fiber Type ◽  
Oxidative Capacity ◽  
Diaphragm Muscle ◽  
Type I ◽  
Specific Force ◽  
Succinate Dehydrogenase Activity ◽  
Cross Sectional ◽  
Fresh Frozen

In aged rats, diaphragm muscle (DIAm) reduced specific force and fiber cross-sectional area, sarcopenia, is selective for vulnerable type IIx and/or IIb DIAm fibers, with type I and IIa fibers being resilient. In humans, the oxidative capacity [as measured by maximum succinate dehydrogenase (SDHmax) activity] of fast-type muscle is reduced with aging, with slow-type muscle being unaffected. We hypothesized that in aged Fischer rat DIAm exhibiting sarcopenia, reduced SDHmax activity would occur in type IIx and/or IIb fibers. Rats obtained from the NIA colony (6, 18, and 24 mo old) were euthanized, and ~2-mm-wide DIAm strips were obtained. For SDHmax and fiber type assessments, DIAm strips were stretched (approximately optimal length), fresh frozen in isopentane, and sectioned on a cryostat at 6 μm. SDHmax, quantified by intensity of nitroblue tetrazolium diformazan precipitation, was assessed in a fiber type-specific manner by comparing serial sections labeled with myosin heavy chain (MyHC) antibodies differentiating type I (MyHCSlow), IIa (MyHC2A), and IIx and/or IIb fibers. Isometric DIAm force and fatigue were assessed in DIAm strips by muscle stimulation with supramaximal pulses at a variety of frequencies (5–100 Hz) delivered in 1-s trains. By 24 mo, DIAm sarcopenia was apparent and SDHmax in type IIx and/or IIb fibers activity was reduced ~35% compared with 6-mo-old control DIAm. These results underscore the remarkable fiber type selectivity of type IIx and/or IIb fibers to age-associated perturbations and suggest that reduced mitochondrial oxidative capacity is associated with DIAm sarcopenia. NEW & NOTEWORTHY We examined the oxidative capacity as measured by maximum succinate dehydrogenase activity in older (18 or 24 mo old) Fischer 344 rat diaphragm muscle (DIAm) compared with young rats (6 mo old). In 24-mo-old rats, SDH activity was reduced in type IIx/b DIAm fibers. These SDH changes were concomitant with sarcopenia (reduced specific force and atrophy of type IIx/b DIAm fibers) at 24 mo old. At 18 mo old, there was no change in SDH activity and no evidence of sarcopenia.

scholarly journals Sex Differences in Cancer Cachexia

2020 ◽  
Vol 18 (6) ◽  
pp. 646-654
Author(s):  
Xiaoling Zhong ◽  
Teresa A. Zimmers
Keyword(s):  
Weight Loss ◽  
Sex Differences ◽  
Cancer Patients ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Fiber Type ◽  
Global Gene Expression ◽  
Skeletal Muscle Wasting ◽  
Progressive Weight Loss ◽  
And Function

Abstract Purpose of Review Cachexia, a feature of cancer and other chronic diseases, is marked by progressive weight loss and skeletal muscle wasting. This review aims to highlight the sex differences in manifestations of cancer cachexia in patients, rodent models, and our current understanding of the potential mechanisms accounting for these differences. Recent Findings Male cancer patients generally have higher prevalence of cachexia, greater weight loss or muscle wasting, and worse outcomes compared with female cancer patients. Knowledge is increasing about sex differences in muscle fiber type and function, mitochondrial metabolism, global gene expression and signaling pathways, and regulatory mechanisms at the levels of sex chromosomes vs. sex hormones; however, it is largely undetermined how such sex differences directly affect the susceptibility to stressors leading to muscle wasting in cancer cachexia. Summary Few studies have investigated basic mechanisms underlying sex differences in cancer cachexia. A better understanding of sex differences would improve cachexia treatment in both sexes.

Oxidative stress does not influence weight loss induced by aerobic training in adults: randomized clinical trials

2020 ◽  
Vol 60 (6) ◽  
Author(s):  
Glêbia A. Cardoso ◽  
Mateus D. Ribeiro ◽  
Ana P. Ferreira ◽  
Yohanna de Oliveira ◽  
Thiago de O. Medeiros ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Weight Loss ◽  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Aerobic Training
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