Muscle oxidative capacity during IL-6-dependent cancer cachexia

White, James P.; Baltgalvis, Kristen A.; Puppa, Melissa; Sato, Shuichi; Baynes, John W.; Carson, James A.

doi:10.1152/ajpregu.00300.2010

Cited by 134 publications

(213 citation statements)

References 61 publications

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“…In the present study, a reduction in the expression levels of COX IV and Cyto C was observed concomitantly with the downregulation of Mfn2. COX IV and Cyto C are proteins of the mitochondrial respiratory chain and their loss results in reduced ATP formation and mitochondrial dysfunction (11). Therefore, it is possible that cancer cachexia induces the downregulation of Mfn2 in skeletal muscle cells, leading to mitochondrial dysfunction and thereafter muscle mass loss.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of mitochondrial fission has been shown to inhibit muscle loss during fasting (11,15). In addition, downregulation of Mfn2 has been observed in the muscle of obese and non-obese type 2 diabetic subjects (16,17), and decreased mRNA expression levels of Mfn2 were observed in the skeletal muscle of tumor-bearing mice with severe cachexia (11). These results suggested that Mfn2 is involved in muscle wasting associated with diseases such as cancer cachexia.…”

Section: Introductionmentioning

confidence: 94%

“…2G). The mitochondrial proteins COX IV and Cyto C are two key proteins of the mitochondrial respiratory chain, which has a critical role in mitochondrial function (11). The expression levels of COX IV and Cyto C have been used to assess the mitochondrial function of cells in previous studies (11,24).…”

Section: Expression Of Mfn2 Is Downregulated In Tnf-α-induced Myotubementioning

confidence: 99%

“…A system of pro-fusion and pro-fission proteins regulates mitochondrial morphology and subcellular localization (9,10). The fusion proteins mitofusin-1 (Mfn1) and mitofusin-2 (Mfn2) promote mitochondrial elongation and activity (11). As a major determinant of the fusion process, Mfn2 is a large GTPase that is integral to the mitochondrial outer membrane (12).…”

Section: Introductionmentioning

confidence: 99%

“…Mfn2 is robustly expressed in muscle cells and its insufficiency has been associated with the fragmentation of the mitochondrial network, which is essential for the normal mitochondrial function (14). Inhibition of mitochondrial fission has been shown to inhibit muscle loss during fasting (11,15). In addition, downregulation of Mfn2 has been observed in the muscle of obese and non-obese type 2 diabetic subjects (16,17), and decreased mRNA expression levels of Mfn2 were observed in the skeletal muscle of tumor-bearing mice with severe cachexia (11).…”

Section: Introductionmentioning

confidence: 99%

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Mitofusin-2 prevents skeletal muscle wasting in cancer cachexia

Zhang

Jiang

et al. 2016

Oncology Letters

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Abstract. Cancer cachexia remains a leading cause of morbidity and mortality worldwide, despite extensive research and clinical trials. The prominent clinical feature of cancer cachexia is the continuous loss of skeletal muscle that cannot be fully reversed by conventional nutritional support, and that leads to progressive functional impairment. The mechanism underlying muscle loss in patients with cachexia is poorly understood. The present study analyzed 21 cancer patients with or without cachexia, and demonstrated that mitofusin-2 (Mfn2) was downregulated in the rectus abdominis of patients with cachexia, which was associated with body weight loss. In vitro cell experiments indicated that loss of Mfn2 was associated with atrophy of the C2C12 mouse myoblast cell line. Furthermore, in vivo animal experiments demonstrated that cachexia decreased gastrocnemius muscle mass and Mfn2 expression, and overexpression of Mfn2 in gastrocnemius muscle was able to partially attenuate cachexia-induced gastrocnemius muscle loss. The results of the present study suggested that Mfn2 is involved in cachexia-induced muscle loss and may serve as a potential target for therapy of cachexia. IntroductionCachexia, which is the loss of body mass that cannot be reversed by nutrition, is frequently observed in patients with cancer. Cancer cachexia is a leading cause of morbidity and mortality worldwide (1). The prominent clinical feature of cancer cachexia is the continuous loss of skeletal muscle that cannot be fully reversed by conventional nutritional support, leading to progressive functional impairment (2,3). The skeletal muscle loss is associated with a reduced quality of life, as well as poor survival (4). The pathophysiology of cancer cachexia is characterized by a negative protein and energy balance (5); however, the underlying mechanism remains largely unknown. Previous studies have demonstrated that numerous signaling molecules and transcription factors are involved in the regulation of skeletal muscle mass (6,7).Mitochondrial function is crucial for the maintenance of the skeletal muscle (8). It has been demonstrated that suppression of mitochondrial function is sufficient to cause muscle wasting in adult animals (8). Mitochondrial function requires the coordination of mitochondrial fusion and fission processes that are referred to as mitochondrial dynamics (9,10). A system of pro-fusion and pro-fission proteins regulates mitochondrial morphology and subcellular localization (9,10). The fusion proteins mitofusin-1 (Mfn1) and mitofusin-2 (Mfn2) promote mitochondrial elongation and activity (11). As a major determinant of the fusion process, Mfn2 is a large GTPase that is integral to the mitochondrial outer membrane (12). It is essential for mitochondrial fusion during embryonic development and neuronal differentiation (13). In humans, mutations in the Mfn2 locus have been associated with numerous diseases, including Charcot-Marie-Tooth type 2A neuropathy, diabetes and Alzheimer's disease (14). Mfn2 is robustly expressed in mus...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Expression Of Mfn2 Is Downregulated In Tnf-α-induced Myotubementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mitofusin-2 prevents skeletal muscle wasting in cancer cachexia

Zhang

Jiang

et al. 2016

Oncology Letters

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Preserved muscle oxidative metabolic phenotype in newly diagnosed non‐small cell lung cancer cachexia

Kamp

Gosker

Lagarde

et al. 2015

J cachexia sarcopenia muscle

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BackgroundCachexia augments cancer-related mortality and has devastating effects on quality of life. Pre-clinical studies indicate that systemic inflammation-induced loss of muscle oxidative phenotype (OXPHEN) stimulates cancer-induced muscle wasting. The aim of the current proof of concept study is to validate the presence of muscle OXPHEN loss in newly diagnosed patients with lung cancer, especially in those with cachexia.MethodsQuadriceps muscle biopsies of comprehensively phenotyped pre-cachectic (n = 10) and cachectic (n = 16) patients with non-small cell lung cancer prior to treatment were compared with healthy age-matched controls (n = 22). OXPHEN was determined by assessing muscle fibre type distribution (immunohistochemistry), enzyme activity (spectrophotometry), and protein expression levels of mitochondrial complexes (western blot) as well as transcript levels of (regulatory) oxidative genes (quantitative real-time PCR). Additionally, muscle fibre cross-sectional area (immunohistochemistry) and systemic inflammation (multiplex analysis) were assessed.ResultsMuscle fibre cross-sectional area was smaller, and plasma levels of interleukin 6 were significantly higher in cachectic patients compared with non-cachectic patients and healthy controls. No differences in muscle fibre type distribution or oxidative and glycolytic enzyme activities were observed between the groups. Mitochondrial protein expression and gene expression levels of their regulators were also not different.ConclusionMuscle OXPHEN is preserved in newly diagnosed non-small cell lung cancer and therefore not a primary trigger of cachexia in these patients.

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Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin‐induced cachexia

Conte

Camerino

Mele

et al. 2017

J cachexia sarcopenia muscle

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BackgroundCachexia is a wasting condition associated with cancer types and, at the same time, is a serious and dose‐limiting side effect of cancer chemotherapy. Skeletal muscle loss is one of the main characteristics of cachexia that significantly contributes to the functional muscle impairment. Calcium‐dependent signaling pathways are believed to play an important role in skeletal muscle decline observed in cachexia, but whether intracellular calcium homeostasis is affected in this situation remains uncertain. Growth hormone secretagogues (GHS), a family of synthetic agonists of ghrelin receptor (GHS‐R1a), are being developed as a therapeutic option for cancer cachexia syndrome; however, the exact mechanism by which GHS interfere with skeletal muscle is not fully understood.MethodsBy a multidisciplinary approach ranging from cytofluorometry and electrophysiology to gene expression and histology, we characterized the calcium homeostasis in fast‐twitch extensor digitorum longus (EDL) muscle of adult rats with cisplatin‐induced cachexia and established the potential beneficial effects of two GHS (hexarelin and JMV2894) at this level. Additionally, in vivo measures of grip strength and of ultrasonography recordings allowed us to evaluate the functional impact of GHS therapeutic intervention.ResultsCisplatin‐treated EDL muscle fibres were characterized by a ~18% significant reduction of the muscle weight and fibre diameter together with an up‐regulation of atrogin1/Murf‐1 genes and a down‐regulation of Pgc1‐a gene, all indexes of muscle atrophy, and by a two‐fold increase in resting intracellular calcium, [Ca2+]i, compared with control rats. Moreover, the amplitude of the calcium transient induced by caffeine or depolarizing high potassium solution as well as the store‐operated calcium entry were ~50% significantly reduced in cisplatin‐treated rats. Calcium homeostasis dysregulation parallels with changes of functional ex vivo (excitability and resting macroscopic conductance) and in vivo (forelimb force and muscle volume) outcomes in cachectic animals. Administration of hexarelin or JMV2894 markedly reduced the cisplatin‐induced alteration of calcium homeostasis by both common as well as drug‐specific mechanisms of action. This effect correlated with muscle function preservation as well as amelioration of various atrophic indexes, thus supporting the functional impact of GHS activity on calcium homeostasis.ConclusionsOur findings provide a direct evidence that a dysregulation of calcium homeostasis plays a key role in cisplatin‐induced model of cachexia gaining insight into the etiopathogenesis of this form of muscle wasting. Furthermore, our demonstration that GHS administration efficaciously prevents cisplatin‐induced calcium homeostasis alteration contributes to elucidate the mechanism of action through which GHS could potentially ameliorate chemotherapy‐associated cachexia.

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Muscle oxidative capacity during IL-6-dependent cancer cachexia

Cited by 134 publications

References 61 publications

Mitofusin-2 prevents skeletal muscle wasting in cancer cachexia

Mitofusin-2 prevents skeletal muscle wasting in cancer cachexia

Preserved muscle oxidative metabolic phenotype in newly diagnosed non‐small cell lung cancer cachexia

Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin‐induced cachexia

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