scholarly journals Muscle alterations in the development and progression of cancer-induced muscle atrophy: a review

2020 ◽  
Vol 128 (1) ◽  
pp. 25-41 ◽  
Author(s):  
Megan E. Rosa-Caldwell ◽  
Dennis K. Fix ◽  
Tyrone A. Washington ◽  
Nicholas P. Greene
Keyword(s):  
Cancer Patients ◽  
Protein Turnover ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Cell Function ◽  
Developmental Stages ◽  
Muscle Loss ◽  
Inflammatory Signaling ◽  
Mortality And Morbidity ◽  
Cancer Types

Cancer cachexia—cancer-associated body weight and muscle loss—is a significant predictor of mortality and morbidity in cancer patients across a variety of cancer types. However, despite the negative prognosis associated with cachexia onset, there are no clinical therapies approved to treat or prevent cachexia. This lack of treatment may be partially due to the relative dearth of literature on mechanisms occurring within the muscle before the onset of muscle wasting. Therefore, the purpose of this review is to compile the current scientific literature on mechanisms contributing to the development and progression of cancer cachexia, including protein turnover, inflammatory signaling, and mitochondrial dysfunction. We define “development” as changes in cell function occurring before the onset of cachexia and “progression” as alterations to cell function that coincide with the exacerbation of muscle wasting. Overall, the current literature suggests that multiple aspects of cellular function, such as protein turnover, inflammatory signaling, and mitochondrial quality, are altered before the onset of muscle loss during cancer cachexia and clearly highlights the need to study more thoroughly the developmental stages of cachexia. The studying of these early aberrations will allow for the development of effective therapeutics to prevent the onset of cachexia and improve health outcomes in cancer patients.

scholarly journals JNK signaling contributes to skeletal muscle wasting and protein turnover in pancreatic cancer cachexia

2020 ◽  
Vol 491 ◽  
pp. 70-77 ◽  
Author(s):  
Scott E. Mulder ◽  
Aneesha Dasgupta ◽  
Ryan J. King ◽  
Jaime Abrego ◽  
Kuldeep S. Attri ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Pancreatic Cancer ◽  
Protein Turnover ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Jnk Signaling ◽  
Skeletal Muscle Wasting

scholarly journals Muscle wasting in the critically ill patient: how to minimise subsequent disability

2020 ◽  
Vol 81 (4) ◽  
pp. 1-9
Author(s):  
Luke Flower ◽  
Zudin Puthucheary
Keyword(s):  
Critically Ill ◽  
Psychological Health ◽  
Critically Ill Patients ◽  
Muscle Wasting ◽  
Critically Ill Patient ◽  
Muscle Loss ◽  
Post Discharge ◽  
Mortality And Morbidity ◽  
Muscle Breakdown ◽  
Physical And Psychological Health

Muscle wasting in critically ill patients is the most common complication associated with critical care. It has significant effects on physical and psychological health, mortality and quality of life. It is most severe in the first few days of illness and in the most critically unwell patients, with muscle loss estimated to occur at 2–3% per day. This muscle loss is likely a result of a reduction in protein synthesis relative to muscle breakdown, resulting in altered protein homeostasis. The associated weakness is associated with in an increase in both short- and long-term mortality and morbidity, with these detrimental effects demonstrated up to 5 years post discharge. This article highlights the significant impact that muscle wasting has on critically ill patients' outcomes, how this can be reduced, and how this might change in the future.

scholarly journals Modulating Metabolism to Improve Cancer-Induced Muscle Wasting

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Fabio Penna ◽  
Riccardo Ballarò ◽  
Marc Beltrá ◽  
Serena De Lucia ◽  
Paola Costelli
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Cancer Patients ◽  
Clinical Studies ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Muscle Metabolism ◽  
Preclinical Models ◽  
Oncologic Patients ◽  
Clinical Conditions

Muscle wasting is one of the main features of cancer cachexia, a multifactorial syndrome frequently occurring in oncologic patients. The onset of cachexia is associated with reduced tolerance and response to antineoplastic treatments, eventually leading to clinical conditions that are not compatible with survival. Among the mechanisms underlying cachexia, protein and energy dysmetabolism play a major role. In this regard, several potential treatments have been proposed, mainly on the basis of promising results obtained in preclinical models. However, at present, no treatment yet reached validation to be used in the clinical practice, although several drugs are currently tested in clinical trials for their ability to improve muscle metabolism in cancer patients. Along this line, the results obtained in both experimental and clinical studies clearly show that cachexia can be effectively approached by a multidirectional strategy targeting nutrition, inflammation, catabolism, and inactivity at the same time. In the present study, approaches aimed to modulate muscle metabolism in cachexia will be reviewed.

scholarly journals Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 597 ◽  
Author(s):  
Vanina Romanello ◽  
Marco Scalabrin ◽  
Mattia Albiero ◽  
Bert Blaauw ◽  
Luca Scorrano ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Skeletal Muscles ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Premature Death ◽  
Muscle Loss ◽  
Mitochondrial Network ◽  
Double Knockout ◽  
Physiological Relevance ◽  
Simultaneous Inhibition

The maintenance of muscle mass and its ability to function relies on a bioenergetic efficient mitochondrial network. This network is highly impacted by fusion and fission events. We have recently shown that the acute deletion of the fusion protein Opa1 induces muscle atrophy, systemic inflammatory response, precocious epithelial senescence, and premature death that are caused by muscle-dependent secretion of FGF21. However, both fusion and fission machinery are suppressed in aging sarcopenia, cancer cachexia, and chemotherapy-induced muscle wasting. We generated inducible muscle-specific Opa1 and Drp1 double-knockout mice to address the physiological relevance of the concomitant impairment of fusion and fission machinery in skeletal muscle. Here we show that acute ablation of Opa1 and Drp1 in adult muscle causes the accumulation of abnormal and dysfunctional mitochondria, as well as the inhibition of autophagy and mitophagy pathways. This ultimately results in ER stress, muscle loss, and the reduction of force generation. However, the simultaneous inhibition of the fission protein Drp1 when Opa1 is absent alleviates FGF21 induction, oxidative stress, denervation, and inflammation rescuing the lethal phenotype of Opa1 knockout mice, despite the presence of any muscle weakness. Thus, the simultaneous inhibition of fusion and fission processes mitigates the detrimental effects of unbalanced mitochondrial fusion and prevents the secretion of pro-senescence factors.

scholarly journals MMP12 Knockout Prevent Weight and Muscle Loss Induced by Cancer Cachexia

2021 ◽  
Author(s):  
Lingbi Jiang ◽  
Mingming Yang ◽  
Shihui He ◽  
Zhengyang Li ◽  
Haobin Li ◽  
...  
Keyword(s):  
Weight Loss ◽  
Interleukin 6 ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Critical Role ◽  
Muscle Loss ◽  
Glycolipid Metabolism ◽  
Patients With Cancer

AbstractWeight loss and muscle wasting can have devastating impacts on survival and quality of life of patients with cancer cachexia. Here, we have established a hybrid mouse of ApcMin/+ mice and MMP12 knockout mice (ApcMin/+; MMP12-/-) and found that knockout MMP12 can suppress the weight and muscle loss of ApcMin/+ mice. In detail, we found that interleukin 6 was highly upregulated in the serum of cancer patients and MMP12 was increased in muscle of tumor-bearing mice. Interestingly, the interleukin 6 secreted by tumor cells led to MMP12 overexpression in the macrophages, which further resulted in degradation of insulin and insulin-like growth factor 1 and interruption of glycolipid metabolism. Notably, depletion of MMP12 prevented weight loss of ApcMin/+ mice. Our study uncovers the critical role of MMP12 in controlling weight and highlights the great potential of MMP12 in the treatment of cancer cachexia.

Cancer cachexia and diabetes: similarities in metabolic alterations and possible treatment,

2014 ◽  
Vol 39 (6) ◽  
pp. 643-653 ◽  
Author(s):  
Stéphanie Chevalier ◽  
Samaneh Farsijani
Keyword(s):  
Amino Acid ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Muscle Protein ◽  
Human Cancer ◽  
Muscle Protein Synthesis ◽  
Glucose Disposal ◽  
Muscle Loss ◽  
Amino Acid Availability ◽  
Age Related

Cancer cachexia is a metabolic syndrome featuring many alterations typical of type 2 diabetes (T2D). While muscle wasting is a hallmark of cachexia, epidemiological evidence also supports an accelerated age-related muscle loss in T2D. Insulin resistance manifests in both conditions and impairs glucose disposal and protein anabolism by tissues. A greater contribution of gluconeogenesis to glucose production may limit amino acid availability for muscle protein synthesis, further aggravating muscle loss. In the context of inter-dependence between glucose and protein metabolism, the present review summarizes the current state of knowledge on alterations that may lead to muscle wasting in human cancer. By highlighting the similarities with T2D, a disease that has been more extensively studied, the objective of this review is to provide a better understanding of the pathophysiology of cancer cachexia and to consider potential treatments usually targeted for T2D. Nutritional approaches aimed at stimulating protein anabolism might include specially formulated food with optimal protein and amino acid composition. Because the gradual muscle loss in T2D may be attenuated by diabetes treatment, anti-diabetic drugs might be considered in cachexia treatment. Metformin emerges as a choice candidate as it acts both on reducing gluconeogenesis and improving insulin sensitivity, and has demonstrated tumour suppressor properties in multiple cancer types. Such a multimodal approach to slow or reverse muscle wasting in cachexia warrants further investigation.

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.

scholarly journals Cancer-Associated Muscle Wasting—Candidate Mechanisms and Molecular Pathways

2020 ◽  
Vol 21 (23) ◽  
pp. 9268
Author(s):  
Victoria S. Armstrong ◽  
Liam W. Fitzgerald ◽  
Oliver F. Bathe
Keyword(s):  
Cancer Patients ◽  
Poor Prognosis ◽  
Muscle Wasting ◽  
Nutritional Intervention ◽  
Therapeutic Interventions ◽  
Future Research ◽  
Molecular Pathways ◽  
Muscle Loss ◽  
Age Related ◽  
Growing Body

Excessive muscle loss is commonly observed in cancer patients and its association with poor prognosis has been well-established. Cancer-associated sarcopenia differs from age-related wasting in that it is not responsive to nutritional intervention and exercise. This is related to its unique pathogenesis, a result of diverse and interconnected mechanisms including inflammation, disordered metabolism, proteolysis and autophagy. There is a growing body of evidence that suggests that the tumor is the driver of muscle wasting by its elaboration of mediators that influence each of these pro-sarcopenic pathways. In this review, evidence for these tumor-derived factors and putative mechanisms for inducing muscle wasting will be reviewed. Potential targets for future research and therapeutic interventions will also be reviewed.

scholarly journals Displaced Myonuclei in Cancer Cachexia Suggest Altered Innervation

2020 ◽  
Vol 21 (3) ◽  
pp. 1092 ◽  
Author(s):  
Nissrine Daou ◽  
Medhi Hassani ◽  
Emidio Matos ◽  
Gabriela Salim De Castro ◽  
Raquel Galvao Figueredo Costa ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Healthy Subjects ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Muscle Fibers ◽  
Progressive Increase ◽  
Tumor Bearing ◽  
Central Nuclei ◽  
Bona Fide ◽  
Motor Neuron Loss

An idiopathic myopathy characterized by central nuclei in muscle fibers, a hallmark of muscle regeneration, has been observed in cancer patients. In cancer cachexia skeletal muscle is incapable of regeneration, consequently, this observation remains unaccounted for. In C26-tumor bearing, cachectic mice, we observed muscle fibers with central nuclei in the absence of molecular markers of bona fide regeneration. These clustered, non-peripheral nuclei were present in NCAM-expressing muscle fibers. Since NCAM expression is upregulated in denervated myofibers, we searched for additional makers of denervation, including AchRs, MUSK, and HDAC. This last one being also consistently upregulated in cachectic muscles, correlated with an increase of central myonuclei. This held true in the musculature of patients suffering from gastrointestinal cancer, where a progressive increase in the number of central myonuclei was observed in weight stable and in cachectic patients, compared to healthy subjects. Based on all of the above, the presence of central myonuclei in cancer patients and animal models of cachexia is consistent with motor neuron loss or NMJ perturbation and could underlie a previously neglected phenomenon of denervation, rather than representing myofiber damage and regeneration in cachexia. Similarly to aging, denervation-dependent myofiber atrophy could contribute to muscle wasting in cancer cachexia.

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

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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