Mathematical Model of Muscle Wasting in Cancer Cachexia

Cancer cachexia is a debilitating condition characterized by an extreme loss of skeletal muscle mass, which negatively impacts patients’ quality of life, reduces their ability to sustain anti-cancer therapies, and increases the risk of mortality. Recent discoveries have identified the myostatin/activin A/ActRIIB pathway as critical to muscle wasting by inducing satellite cell quiescence and increasing muscle-specific ubiquitin ligases responsible for atrophy. Remarkably, pharmacological blockade of the ActRIIB pathway has been shown to reverse muscle wasting and prolong the survival time of tumor-bearing animals. To explore the implications of this signaling pathway and potential therapeutic targets in cachexia, we construct a novel mathematical model of muscle tissue subjected to tumor-derived cachectic factors. The model formulation tracks the intercellular interactions between cancer cell, satellite cell, and muscle cell populations. The model is parameterized by fitting to colon-26 mouse model data, and the analysis provides insight into tissue growth in healthy, cancerous, and post-cachexia treatment conditions. Model predictions suggest that cachexia fundamentally alters muscle tissue health, as measured by the stem cell ratio, and this is only partially recovered by anti-cachexia treatment. Our mathematical findings suggest that after blocking the myostatin/activin A pathway, partial recovery of cancer-induced muscle loss requires the activation and proliferation of the satellite cell compartment with a functional differentiation program.

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Mathematical Model of Muscle Wasting in Cancer Cachexia

10.1101/2020.03.30.016709 ◽

2020 ◽

Author(s):

Suzan Farhang-Sardroodi ◽

Kathleen P. Wilkie

Keyword(s):

Mathematical Model ◽

Satellite Cell ◽

Muscle Tissue ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Tissue Growth ◽

Colon 26 ◽

Treatment Conditions ◽

Risk Of Mortality ◽

Pharmacological Blockade

Cancer cachexia is a debilitating condition characterized by an extreme loss of skeletal muscle mass which negatively impacts patient’s quality of life, reduces their ability to sustain anticancer therapies, and increases the risk of mortality. Recent discoveries have identified the myostatin/activin-ActRIIB pathway as critical to muscle wasting by inducing satellite cell quiescence and increasing muscle-specific ubiquitin ligases responsible for atrophy. Remarkably, pharmacological blockade of the ActRIIB pathway has shown to reverse muscle wasting and prolong the survival time of tumor-bearing animals. To explore the implications of this signaling pathway and potential therapeutic targets in cachexia, we construct a novel mathematical model of muscle tissue subjected to tumor-derived cachexic factors. The model formulation tracks the intercellular interactions between cancer, satellite cell, and muscle cell populations. The model is parameterized by fitting to colon-26 mouse model data, and analysis provides insight into tissue growth in healthy, cancerous, and post-treatment conditions. Model predictions suggest that cachexia fundamentally alters muscle tissue health, as measured by the stem cell ratio, and this is only partially recovered by anti-cachexia treatment. Our mathematical findings suggest that the activation and proliferation of satellite cells, after blocking the myostatin/activin B pathway, is required to partially recover cancer-induced muscle loss.

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Stage-specific muscle wasting mechanisms in a novel cancer cachexia mouse model for ovarian granulosa cell tumor

10.1101/2020.06.16.154385 ◽

2020 ◽

Author(s):

Yaqi Zhang ◽

Jie Zhu ◽

So-Youn Kim ◽

Megan M Romero ◽

Kelly A Even ◽

...

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Granulosa Cell ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Activin A ◽

Mice Model ◽

E3 Ligases ◽

Ovarian Granulosa Cell ◽

Specific Muscle

AbstractCachexia is a progressive muscle wasting syndrome that increases mortality risk in cancer patients, while there are still no effective treatment due to the complexity of syndrome and the lack of preclinical models. We identified a transgenic mice model with ovarian granulosa cell tumors mimic the progression of cachexia seen in humans, including drastic weight loss, skeletal muscle wasting and increased serum cachexia biomarker activin A and GDF15. Hypercatabolism was detected in skeletal muscle, having upregulation of E3 ligases Atrogin-1 and Murf-1. Our cachexia model exhibited stage-specific muscle wasting mechanisms. At precachexia stage, elevation of activin A activates p38 MAPK. Inhibition of activin A with Follistatin reversed weight loss at precachexia stage. At cachexia stage, energy stress in skeletal muscle activates AMPKα and leads to upregulation of FoxO3. Our results indicate this novel preclinical cancer cachexia model is exploitable for studying pathophysiological mechanisms and testing therapeutic agents of cachexia.

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Chemotherapy-induced muscle wasting: association with NF-κB and cancer cachexia

European Journal of Translational Myology ◽

10.4081/ejtm.2018.7590 ◽

2018 ◽

Vol 28 (2) ◽

Cited By ~ 34

Author(s):

Jeffrey S. Damrauer ◽

Michael E. Stadler ◽

Swarnali Acharyya ◽

Albert S. Baldwin ◽

Marion E. Couch ◽

...

Keyword(s):

Cancer Cachexia ◽

Muscle Wasting ◽

Ubiquitin Proteasome System ◽

Tumor Burden ◽

Cancer Treatments ◽

Colon 26 ◽

Reduce Tumor Burden ◽

High Incidence ◽

Ubiquitin Proteasome ◽

Chemotherapy Agents

A compounding feature of greater than 50% of all cancers is the high incidence of the cachexia syndrome, a complex metabolic disorder characterized by extreme weight loss due mainly to the gross depletion of skeletal muscle tissue. Although studies into the cause of cancer cachexia has spanned over multiple decades, little is known about the effects of various cancer treatments themselves on cachexia. For example, chemotherapy agents induce side effects such as nausea and anorexia, but these symptoms do not fully account for the changes seen with cancer cachexia. In this study we examine the effects of chemotherapeutic compounds, specifically, cisplatin in the colon-26 adenocarcinoma model of cancer cachexia. We find that although cisplatin is able to reduce tumor burden as expected, muscle wasting in mice nevertheless persists. Strikingly, cisplatin alone was seen to regulate muscle atrophy, which was independent of the commonly implicated ubiquitin proteasome system. Finally, we show that cisplatin is able to induce NF-κB activity in both mouse muscles and myotube cultures, suggesting that an additional side effect of cancer treatment is the regulation of muscle wasting that may be mediated through activation of the NF-κB signaling pathway.

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Nonmuscle Tissues Contribution to Cancer Cachexia

Mediators of Inflammation ◽

10.1155/2015/182872 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 27

Author(s):

Josep M. Argilés ◽

Britta Stemmler ◽

Francisco J. López-Soriano ◽

Silvia Busquets

Keyword(s):

Weight Loss ◽

Body Weight ◽

Adipose Tissue ◽

Muscle Tissue ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Body Weight Loss ◽

Present Review ◽

Recent Developments ◽

The Impact

Cachexia is a syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting, and inflammation, being often associated with anorexia. In spite of the fact that muscle tissue represents more than 40% of body weight and seems to be the main tissue involved in the wasting that occurs during cachexia, recent developments suggest that tissues/organs such as adipose (both brown and white), brain, liver, gut, and heart are directly involved in the cachectic process and may be responsible for muscle wasting. This suggests that cachexia is indeed a multiorgan syndrome. Bearing all this in mind, the aim of the present review is to examine the impact of nonmuscle tissues in cancer cachexia.

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The Role of Systemic Inflammation in Cancer-Associated Muscle Wasting and Rationale for Exercise as a Therapeutic Intervention

JCSM Clinical Reports ◽

10.17987/jcsm-cr.v3i2.65 ◽

2018 ◽

Vol 3 (2) ◽

Cited By ~ 4

Author(s):

Calvin Lloyd Cole ◽

Ian R. Kleckner ◽

Aminah Jatoi ◽

Edward Schwarz ◽

Richard F. Dunne

Keyword(s):

Skeletal Muscle ◽

Systemic Inflammation ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Activin A ◽

Therapeutic Interventions ◽

Muscle Quality ◽

Patients With Cancer ◽

Skeletal Muscle Wasting ◽

The Impact

Progressive skeletal muscle wasting in cancer cachexia involves a process of dysregulated protein synthesis and breakdown. This catabolism may be the result of mal-nutrition, and an upregulation of both pro-inflammatory cytokines and the ubiquitin proteasome pathway (UPP), which can subsequently increase myostatin and activin A release. The skeletal muscle wasting associated with cancer cachexia is clinically significant, it can contribute to treatment toxicity or the premature discontinuation of treatments resulting in increases in morbidity and mortality. Thus, there is a need for further investigation into the pathophysiology of muscle wasting in cancer cachexia to develop effective prophylactic and therapeutic interventions. Several studies have identified a central role for chronic-systemic inflammation in initiating and perpetuating muscle wasting in patients with cancer. Interestingly, while exercise has shown efficacy in improving muscle quality, only recently have investigators begun to assess the impact that exercise has on chronic-systemic inflammation. To put this new information into context with established paradigms, here we review several biological pathways (e.g. dysfunctional inflammatory response, hypothalamus pituitary adrenal axis, and increased myostatin/activin A activity) that may be responsible for the muscle wasting in patients with cancer. Additionally, we discuss the potential impact that exercise has on these pathways in the treatment of cancer cachexia. Exercise is an attractive intervention for muscle wasting in this population, partially because it disrupts chronic-systemic inflammation mediated catabolism. Most importantly, exercise is a potent stimulator of muscle synthesis, and therefore this therapy may reverse muscle damage caused by cancer cachexia.

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Aerobic Exercise Ameliorates Cancer Cachexia-Induced Muscle Wasting through Adiponectin Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms22063110 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3110

Author(s):

Makoto Morinaga ◽

Naoki Sako ◽

Mari Isobe ◽

Sachiko Lee-Hotta ◽

Hideshi Sugiura ◽

...

Keyword(s):

Aerobic Exercise ◽

Muscle Atrophy ◽

Molecular Basis ◽

Cancer Cachexia ◽

Molecular Mechanisms ◽

Muscle Wasting ◽

C2c12 Myotubes ◽

Cellular Model ◽

Muscle Loss ◽

Colon 26

Cachexia is a multifactorial syndrome characterized by muscle loss that cannot be reversed by conventional nutritional support. To uncover the molecular basis underlying the onset of cancer cachectic muscle wasting and establish an effective intervention against muscle loss, we used a cancer cachectic mouse model and examined the effects of aerobic exercise. Aerobic exercise successfully suppressed muscle atrophy and activated adiponectin signaling. Next, a cellular model for cancer cachectic muscle atrophy using C2C12 myotubes was prepared by treating myotubes with a conditioned medium from a culture of colon-26 cancer cells. Treatment of the atrophic myotubes with recombinant adiponectin was protective against the thinning of cells through the increased production of p-mTOR and suppression of LC3-II. Altogether, these findings suggest that the activation of adiponectin signaling could be part of the molecular mechanisms by which aerobic exercise ameliorates cancer cachexia-induced muscle wasting.

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