Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour‐bearing mice

Brown, Jacob L.; Rosa‐Caldwell, Megan E.; Lee, David E.; Blackwell, Thomas A.; Brown, Lemuel A.; Perry, Richard; Haynie, Wesley S.; Hardee, Justin P.; Carson, James A.; Wiggs, Michael P.; Washington, Tyrone A.

doi:10.1002/jcsm.12232

Cited by 212 publications

(381 citation statements)

References 67 publications

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“…Oxidative stress, the imbalance between pro‐oxidant generation and antioxidant defence, has been implicated in pathological conditions of skeletal muscle, including sarcopenia, denervation, and cancer cachexia . Excess levels of reactive oxygen species (ROS) impair contractile function of skeletal muscle and activate proteases that are associated with degradation of contractile machinery .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching

Ahn

Ranjit

Premkumar

et al. 2019

J cachexia sarcopenia muscle

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Background Excess reactive oxygen species (ROS) and muscle weakness occur in parallel in multiple pathological conditions. However, the causative role of skeletal muscle mitochondrial ROS (mtROS) on neuromuscular junction (NMJ) morphology and function and muscle weakness has not been directly investigated. Methods We generated mice lacking skeletal muscle‐specific manganese‐superoxide dismutase (m Sod2 KO) to increase mtROS using a cre‐Lox approach driven by human skeletal actin. We determined primary functional parameters of skeletal muscle mitochondrial function (respiration, ROS, and calcium retention capacity) using permeabilized muscle fibres and isolated muscle mitochondria. We assessed contractile properties of isolated skeletal muscle using in situ and in vitro preparations and whole lumbrical muscles to elucidate the mechanisms of contractile dysfunction. Results The m Sod2 KO mice, contrary to our prediction, exhibit a 10–15% increase in muscle mass associated with an ~50% increase in central nuclei and ~35% increase in branched fibres ( P < 0.05). Despite the increase in muscle mass of gastrocnemius and quadriceps, in situ sciatic nerve‐stimulated isometric maximum‐specific force ( N /cm 2 ), force per cross‐sectional area, is impaired by ~60% and associated with increased NMJ fragmentation and size by ~40% ( P < 0.05). Intrinsic alterations of components of the contractile machinery show elevated markers of oxidative stress, for example, lipid peroxidation is increased by ~100%, oxidized glutathione is elevated by ~50%, and oxidative modifications of myofibrillar proteins are increased by ~30% ( P < 0.05). We also find an approximate 20% decrease in the intracellular calcium transient that is associated with specific force deficit. Excess superoxide generation from the mitochondrial complexes causes a deficiency of succinate dehydrogenase and reduced complex‐II‐mediated respiration and adenosine triphosphate generation rates leading to severe exercise intolerance (~10 min vs. ~2 h in wild type, P < 0.05). Conclusions Increased skeletal muscle mtROS is sufficient to elicit NMJ disruption and contractile abnormalities, but not muscle atrophy, suggesting new roles for mitochondrial oxidative stress in maintenance of muscle mass through increased fibre branching.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching

Ahn

Ranjit

Premkumar

et al. 2019

J cachexia sarcopenia muscle

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“…Notably, we now report cancer and chemotherapy acting synergistically, impairing mitochondrial homeostasis from the biogenesis and degradation, to the dynamic processes that modify the mitochondrial network and, in turn, its efficiency (47). Consistently, tumor‐bearing mice exhibited, even if not necessarily simultaneously, reduced levels of PGC‐lα and mitochondrial number, increased mitophagy, and altered mitochondrial dynamics (9, 10, 12). These impairments could lead to altered mitochondrial morphology, reducing oxidative capacity and energy stores (9).…”

Section: Discussionmentioning

confidence: 79%

“…In addition, decreased muscle succinate dehydrogenase (SDH) activity and oxidative fiber proportion were observed in tumor hosts, further supporting the idea that mitochondria could play a central role in cancer‐induced muscle atrophy (9, 11). The observation that mitochondrial alterations precede muscle loss in mice bearing the Lewis lung carcinoma (12) suggests that targeting muscle energetics may prevent or at least delay the onset of muscle wasting.…”

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confidence: 99%

Moderate exercise in mice improves cancer plus chemotherapy‐induced muscle wasting and mitochondrial alterations

et al. 2019

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Cancer cachexia is a multifactorial syndrome characterized by anorexia, body wasting, and muscle and adipose tissue loss, impairing patient's tolerance to anticancer treatments and survival. The aim of the present study was to compare the effects induced in mice by tumor growth alone (C26) or in combination with chemotherapy [C26 oxaliplatin and 5‐fluorouracil (oxfu)] and to evaluate the potential of moderate exercise. Oxfu administration to C26 mice exacerbated muscle wasting and triggered autophagy or mitophagy, decreased protein synthesis, and induced mitochondrial alterations. Exercise in C26 oxfu mice counteracted the loss of muscle mass and strength, partially rescuing autophagy and mitochondrial function. Nevertheless, exercise worsened survival in C26 oxfu mice in late stages of cachexia. In summary, chemotherapy further impinges on cancer‐induced alterations, worsening muscle wasting. An ideal multifactorial and early intervention to prevent cancer cachexia could take advantage of exercise, improving patient's energy metabolism, mobility, and quality of life.—Ballarò, R., Beltrà, M., De Lucia, S., Pin, F., Ranjbar, K., Hulmi, J. J., Costelli, P., Penna, F. Moderate exercise in mice improves cancer plus chemotherapy‐induced muscle wasting and mitochondrial alterations. FASEB J. 33, 5482–5494 (2019). http://www.fasebj.org

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“…Gross observation of mice under aspiration challenge showed that mice became lean with decreased physical activity. These characteristics might be similar to the muscle atrophy induced by cancer and glucocorticoids . Reduced body weight by the aspiration challenge may reflect the lean appearance of mice .…”

Section: Discussionmentioning

confidence: 83%

Aspiration pneumonia induces muscle atrophy in the respiratory, skeletal, and swallowing systems

Komatsu

Okazaki

Ebihara

et al. 2018

J cachexia sarcopenia muscle

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BackgroundRepetition of the onset of aspiration pneumonia in aged patients is common and causes chronic inflammation. The inflammation induces proinflammatory cytokine production and atrophy in the muscles. The proinflammatory cytokines induce muscle proteolysis by activating calpains and caspase‐3, followed by further degradation by the ubiquitin‐proteasome system. Autophagy is another pathway of muscle atrophy. However, little is known about the relationship between aspiration pneumonia and muscle. For swallowing muscles, it is not clear whether they produce cytokines. The main objective of this study was to determine whether aspiration pneumonia induces muscle atrophy in the respiratory (the diaphragm), skeletal (the tibialis anterior, TA), and swallowing (the tongue) systems, and their possible mechanisms.MethodsWe employed a mouse aspiration pneumonia model and computed tomography (CT) scans of aged pneumonia patients. To induce aspiration pneumonia, mice were inoculated with low dose pepsin and lipopolysaccharide solution intra‐nasally 5 days a week. The diaphragm, TA, and tongue were isolated, and total RNA, proteins, and frozen sections were stored. Quantitative real‐time polymerase chain reaction determined the expression levels of proinflammatory cytokines, muscle E3 ubiquitin ligases, and autophagy related genes. Western blot analysis determined the activation of the muscle proteolysis pathway. Frozen sections determined the presence of muscle atrophy. CT scans were used to evaluate the muscle atrophy in aged aspiration pneumonia patients.ResultsThe aspiration challenge enhanced the expression levels of proinflammatory cytokines in the diaphragm, TA, and tongue. Among muscle proteolysis pathways, the aspiration challenge activated caspase‐3 in all the three muscles examined, whereas calpains were activated in the diaphragm and the TA but not in the tongue. Activation of the ubiquitin‐proteasome system was detected in all the three muscles examined. The aspiration challenge activated autophagy in the TA and the tongue, whereas weak or little activation was detected in the diaphragm. The aspiration challenge resulted in a greater proportion of smaller myofibers than in controls in the diaphragm, TA, and tongue, suggesting muscle atrophy. CT scans clearly showed that aspiration pneumonia was followed by muscle atrophy in aged patients.ConclusionsAspiration pneumonia induced muscle atrophy in the respiratory, skeletal, and swallowing systems in a preclinical animal model and in human patients. Diaphragmatic atrophy may weaken the force of cough to expectorate sputum or mis‐swallowed contents. Skeletal muscle atrophy may cause secondary sarcopenia. The atrophy of swallowing muscles may weaken the swallowing function. Thus, muscle atrophy could become a new therapeutic target of aspiration pneumonia.

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Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour‐bearing mice

Cited by 212 publications

References 67 publications

Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching

Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching

Moderate exercise in mice improves cancer plus chemotherapy‐induced muscle wasting and mitochondrial alterations

Aspiration pneumonia induces muscle atrophy in the respiratory, skeletal, and swallowing systems

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