Lewis lung carcinoma regulation of mechanical stretch-induced protein synthesis in cultured myotubes

Gao, Song; Carson, James A.

doi:10.1152/ajpcell.00052.2015

Cited by 37 publications

(62 citation statements)

References 77 publications

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“…8E, treatment with 4‐PBA for 12 h considerably reduced the rate of protein synthesis in cultured myotubes. Studies have shown that the addition of LLC‐CM initially increases protein synthesis, potentially to counter atrophy signals, whereas long‐term (.48 h ) treatment inhibits protein synthesis in myotubes (56). We found a modest up‐regulation in protein synthesis by treatment of myotubes with LLC‐CM.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia

et al. 2016

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Cachexia is a devastating syndrome that causes morbidity and mortality in a large number of patients with cancer. However, the mechanisms of cancer cachexia remain poorly understood. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes stress. The ER responds to this stress through activating certain pathways commonly known as the unfolding protein response (UPR). The main function of UPR is to restore homeostasis, but excessive or prolonged activation of UPR can lead to pathologic conditions. In this study, we examined the role of ER stress and UPR in regulation of skeletal muscle mass in naïve conditions and during cancer cachexia. Our results demonstrate that multiple markers of ER stress are highly activated in skeletal muscle of Lewis lung carcinoma (LLC) and Apc(Min/+) mouse models of cancer cachexia. Treatment of mice with 4-phenylbutyrate (4-PBA), a chemical chaperon and a potent inhibitor of ER stress, significantly reduced skeletal muscle strength and mass in both control and LLC-bearing mice. Blocking the UPR also increased the proportion of fast-type fibers in soleus muscle of both control and LLC-bearing mice. Inhibition of UPR reduced the activity of Akt/mTOR pathway and increased the expression of the components of the ubiquitin-proteasome system and autophagy in LLC-bearing mice. Moreover, we found that the inhibition of UPR causes severe atrophy in cultured myotubes. Our study provides initial evidence that ER stress and UPR pathways are essential for maintaining skeletal muscle mass and strength and for protection against cancer cachexia.-Bohnert, K. R., Gallot, Y. S., Sato, S., Xiong, G., Hindi, S. M., Kumar, A. Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia.

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Section: Resultsmentioning

confidence: 99%

Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia

et al. 2016

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“…Although mTOR, FOXO and NF-κB have well-described roles in cancer-induced wasting and disuse, the regulation of these pathways and their effectors may differ between conditions [170] . To this end, exercise and stretch can also activate muscle NF-κB signaling [255–257] , in addition to activating mTOR by Akt independent signaling [258] . Further research is needed to determine the consequences of simultaneously activating disuse and cachectic signaling pathways in muscle.…”

Section: Cancer Cachexia-induced Regulation Of Skeletal Muscle Oximentioning

confidence: 99%

The emerging role of skeletal muscle oxidative metabolism as a biological target and cellular regulator of cancer-induced muscle wasting

Carson

Hardee

VanderVeen

2016

Seminars in Cell & Developmental Biology

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131

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While skeletal muscle mass is an established primary outcome related to understanding cancer cachexia mechanisms, considerable gaps exist in our understanding of muscle biochemical and functional properties that have recognized roles in systemic health. Skeletal muscle quality is a classification beyond mass, and is aligned with muscle's metabolic capacity and substrate utilization flexibility. This supplies an additional role for the mitochondria in cancer-induced muscle wasting. While the historical assessment of mitochondria content and function during cancer-induced muscle loss was closely aligned with energy flux and wasting susceptibility, this understanding has expanded to link mitochondria dysfunction to cellular processes regulating myofiber wasting. The primary objective of this article is to highlight muscle mitochondria and oxidative metabolism as a biological target of cancer cachexia and also as a cellular regulator of cancer-induced muscle wasting. Initially, we examine the role of muscle metabolic phenotype and mitochondria content in cancer-induced wasting susceptibility. We then assess the evidence for cancer-induced regulation of skeletal muscle mitochondrial biogenesis, dynamics, mitophagy, and oxidative stress. In addition, we discuss environments associated with cancer cachexia that can impact the regulation of skeletal muscle oxidative metabolism. The article also examines the role of cytokine-mediated regulation of mitochondria function regulation, followed by the potential role of cancer-induced hypogonadism. Lastly, a role for decreased muscle use in cancer-induced mitochondrial dysfunction is reviewed.

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“…While AMPK activation by systemic IL-6 also corresponds with mTORC1 suppression in tumor-bearing mice [ 94 ], AMPK inhibition could rescue IL-6-induced suppression of mTORC1 signaling in C 2 C 12 myotubes [ 94 ]. Moreover, inhibition of myotube AMPK activity during LLC treatment improved mTORC1 signaling and protein synthesis [ 95 ]. In contrast to the acute effects of exercise on AMPK activity in healthy skeletal muscle, the chronic activation of AMPK by cachexia or IL-6 overexpression is uncoupled from mitochondrial biogenesis [ 11 , 97 ].…”

Section: Muscle Oxidative Metabolism Regulation Of Protein Synthesmentioning

confidence: 99%

“…While the mechanisms associated with feeding-induced protein synthesis during cancer are starting to emerge, much less is known related to the acute anabolic response to contraction in cachectic muscle. We have reported that mechanoactivation of protein synthesis in stretched myotubes is disrupted by conditioned media from Lewis lung carcinoma (LLC) cells [ 95 ], suggesting that tumor-derived cachectic factors can interfere with mechanical signaling inducing protein synthesis in vitro . In addition, we found that severe cachexia could disrupt the metabolic and anabolic signaling response to a single bout of stimulated concentric muscle contractions [ 110 ].…”

Section: Cancer-induced Anabolic Resistancementioning

confidence: 99%

Linking Cancer Cachexia‐Induced Anabolic Resistance to Skeletal Muscle Oxidative Metabolism

Hardee

Montalvo

Carson

2017

Oxidative Medicine and Cellular Longevity

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Cancer cachexia, a wasting syndrome characterized by skeletal muscle depletion, contributes to increased patient morbidity and mortality. While the intricate balance between protein synthesis and breakdown regulates skeletal muscle mass, the suppression of basal protein synthesis may not account for the severe wasting induced by cancer. Therefore, recent research has shifted to the regulation of “anabolic resistance,” which is the impaired ability of nutrition and exercise to stimulate protein synthesis. Emerging evidence suggests that oxidative metabolism can regulate both basal and induced muscle protein synthesis. While disrupted protein turnover and oxidative metabolism in cachectic muscle have been examined independently, evidence suggests a linkage between these processes for the regulation of cancer-induced wasting. The primary objective of this review is to highlight the connection between dysfunctional oxidative metabolism and cancer-induced anabolic resistance in skeletal muscle. First, we review oxidative metabolism regulation of muscle protein synthesis. Second, we describe cancer-induced alterations in the response to an anabolic stimulus. Finally, we review a role for exercise to inhibit cancer-induced anabolic suppression and mitochondrial dysfunction.

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Lewis lung carcinoma regulation of mechanical stretch-induced protein synthesis in cultured myotubes

Abstract: Gao S, Carson JA. Lewis lung carcinoma regulation of mechanical stretch-induced protein synthesis in cultured myotubes.

Cited by 37 publications

References 77 publications

Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia

Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia

The emerging role of skeletal muscle oxidative metabolism as a biological target and cellular regulator of cancer-induced muscle wasting

Linking Cancer Cachexia‐Induced Anabolic Resistance to Skeletal Muscle Oxidative Metabolism

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