The mechanism by which noncoding RNAs regulate muscle wasting in cancer cachexia

Abstract Cancer cachexia (CC) is a subject of concern because it is a complex metabolic syndrome that accelerates muscle wasting and affects up to 80% of patients with cancer; however, timely diagnostic methods and effective cures are lacking. Although a considerable number of studies have focused on the mechanism of CC-induced muscle atrophy, few novel therapies have been applied in the last decade. In recent years, noncoding RNAs (ncRNAs) have attracted great attention since many differentially expressed ncRNAs in cancer cachectic muscles have been reported to participate in the inhibition of myogenesis and activation of proteolysis. In addition, extracellular vesicles (EVs), which function as ncRNA carriers in intercellular communication, are closely involved in changing ncRNA expression profiles in muscle and promoting the development of muscle wasting; thus, EV-related ncRNAs may represent potential therapeutic targets. This review comprehensively describes the process of ncRNA transmission through EVs and summarizes the pathways and targets of ncRNAs that lead to CC-induced muscle atrophy.

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Altered expression of skeletal muscle myosin isoforms in cancer cachexia

AJP Cell Physiology ◽

10.1152/ajpcell.00154.2002 ◽

2002 ◽

Vol 283 (5) ◽

pp. C1376-C1382 ◽

Cited By ~ 69

Author(s):

Gary M. Diffee ◽

Katherine Kalfas ◽

Sadeeka Al-Majid ◽

Donna O. McCarthy

Keyword(s):

Muscle Atrophy ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Tumor Cell Line ◽

Protein Isoforms ◽

Type I ◽

Myosin Isoforms ◽

Skeletal Muscle Myosin ◽

Altered Expression ◽

Isoform Expression

Cachexia is commonly seen in cancer and is characterized by severe muscle wasting, but little is known about the effect of cancer cachexia on expression of contractile protein isoforms such as myosin. Other causes of muscle atrophy shift expression of myosin isoforms toward increased fast (type II) isoform expression. We injected mice with murine C-26 adenocarcinoma cells, a tumor cell line that has been shown to cause muscle wasting. Mice were killed 21 days after tumor injection, and hindlimb muscles were removed. Myosin heavy chain (MHC) and myosin light chain (MLC) content was determined in muscle homogenates by SDS-PAGE. Body weight was significantly lower in tumor-bearing (T) mice. There was a significant decrease in muscle mass in all three muscles tested compared with control, with the largest decrease occurring in the soleus. Although no type IIb MHC was detected in the soleus samples from control mice, type IIb comprised 19% of the total MHC in T soleus. Type I MHC was significantly decreased in T vs. control soleus muscle. MHC isoform content was not significantly different from control in plantaris and gastrocnemius muscles. These data are the first to show a change in myosin isoform expression accompanying muscle atrophy during cancer cachexia.

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The Adipokines in Cancer Cachexia

International Journal of Molecular Sciences ◽

10.3390/ijms21144860 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4860 ◽

Cited By ~ 1

Author(s):

Michele Mannelli ◽

Tania Gamberi ◽

Francesca Magherini ◽

Tania Fiaschi

Keyword(s):

Insulin Resistance ◽

Cardiovascular Disease ◽

Skeletal Muscle ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Therapeutic Strategies ◽

Skeletal Muscle Wasting ◽

Circulating Levels

Cachexia is a devastating pathology induced by several kinds of diseases, including cancer. The hallmark of cancer cachexia is an extended weight loss mainly due to skeletal muscle wasting and fat storage depletion from adipose tissue. The latter exerts key functions for the health of the whole organism, also through the secretion of several adipokines. These hormones induce a plethora of effects in target tissues, ranging from metabolic to differentiating ones. Conversely, the decrease of the circulating level of several adipokines positively correlates with insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease. A lot of findings suggest that cancer cachexia is associated with changed secretion of adipokines by adipose tissue. In agreement, cachectic patients show often altered circulating levels of adipokines. This review reported the findings of adipokines (leptin, adiponectin, resistin, apelin, and visfatin) in cancer cachexia, highlighting that to study in-depth the involvement of these hormones in this pathology could lead to the development of new therapeutic strategies.

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Amiloride ameliorates muscle wasting in cancer cachexia through inhibiting tumor-derived exosome release

Skeletal Muscle ◽

10.1186/s13395-021-00274-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lin Zhou ◽

Tong Zhang ◽

Wei Shao ◽

Ruohan Lu ◽

Lin Wang ◽

...

Keyword(s):

Muscle Atrophy ◽

Cancer Cachexia ◽

Molecular Mechanisms ◽

Muscle Wasting ◽

Drug Repositioning ◽

Biochemical Analyses ◽

Related Proteins ◽

Metabolic Impairments

Abstract Background Cancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of the amiloride treatment for ameliorating muscle wasting in murine models of cancer cachexia. Methods The CT26 and LLC tumor cells were subcutaneously injected into mice to induce colon cancer cachexia and lung cancer cachexia, respectively. Amiloride was intraperitoneally injected daily once tumors were formed. Cachexia features of the CT26 model and the LLC model were separately characterized by phenotypic, histopathologic and biochemical analyses. Plasma exosomes and muscle atrophy-related proteins were quantitatively analyzed. Integrative NMR-based metabolomic and transcriptomic analyses were conducted to identify significantly altered metabolic pathways and distinctly changed metabolism-related biological processes in gastrocnemius. Results The CT26 and LLC cachexia models displayed prominent cachexia features including decreases in body weight, skeletal muscle, adipose tissue, and muscle strength. The amiloride treatment in tumor-bearing mice distinctly alleviated muscle atrophy and relieved cachexia-related features without affecting tumor growth. Both the CT26 and LLC cachexia mice showed increased plasma exosome densities which were largely derived from tumors. Significantly, the amiloride treatment inhibited tumor-derived exosome release, which did not obviously affect exosome secretion from non-neoplastic tissues or induce observable systemic toxicities in normal healthy mice. Integrative-omics revealed significant metabolic impairments in cachectic gastrocnemius, including promoted muscular catabolism, inhibited muscular protein synthesis, blocked glycolysis, and impeded ketone body oxidation. The amiloride treatment evidently improved the metabolic impairments in cachectic gastrocnemius. Conclusions Amiloride ameliorates cachectic muscle wasting and alleviates cancer cachexia progression through inhibiting tumor-derived exosome release. Our results are beneficial to understanding the underlying molecular mechanisms, shedding light on the potentials of amiloride in cachexia therapy.

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Neurohypophyseal hormones and skeletal muscle: a tale of two faces

European Journal of Translational Myology ◽

10.4081/ejtm.2019.8899 ◽

2020 ◽

Vol 30 (1) ◽

pp. 53-57

Author(s):

Alexandra Benoni ◽

Alessandra Renzini ◽

Giorgia Cavioli ◽

Sergio Adamo

Keyword(s):

Skeletal Muscle ◽

Muscle Atrophy ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Striated Muscle ◽

Cardiac Atrophy ◽

Neurohypophyseal Hormones

The neurohypophyseal hormones vasopressin and oxytocin were invested, in recent years, with novel functions upon striated muscle, regulating its differentiation, trophism, and homeostasis. Recent studies highlight that these hormones not only target skeletal muscle but represent novel myokines. We discuss the possibility of exploiting the muscle hypertrophying activity of oxytocin to revert muscle atrophy, including cancer cachexia muscle wasting. Furthermore, the role of oxytocin in cardiac homeostasis and the possible role of cardiac atrophy as a concause of death in cachectic patients is discussed.

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Lithium Chloride Protects against Sepsis-Induced Skeletal Muscle Atrophy and Cancer Cachexia

Cells ◽

10.3390/cells10051017 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1017

Author(s):

Ji-Hyung Lee ◽

Seon-Wook Kim ◽

Jun-Hyeong Kim ◽

Hyun-Jun Kim ◽

JungIn Um ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Lithium Chloride ◽

Muscle Atrophy ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Therapeutic Effects ◽

In Vivo Models ◽

Skeletal Muscle Wasting ◽

Chloride Treatment

Inflammation-mediated skeletal muscle wasting occurs in patients with sepsis and cancer cachexia. Both conditions severely affect patient morbidity and mortality. Lithium chloride has previously been shown to enhance myogenesis and prevent certain forms of muscular dystrophy. However, to our knowledge, the effect of lithium chloride treatment on sepsis-induced muscle atrophy and cancer cachexia has not yet been investigated. In this study, we aimed to examine the effects of lithium chloride using in vitro and in vivo models of cancer cachexia and sepsis. Lithium chloride prevented wasting in myotubes cultured with cancer cell-conditioned media, maintained the expression of the muscle fiber contractile protein, myosin heavy chain 2, and inhibited the upregulation of the E3 ubiquitin ligase, Atrogin-1. In addition, it inhibited the upregulation of inflammation-associated cytokines in macrophages treated with lipopolysaccharide. In the animal model of sepsis, lithium chloride treatment improved body weight, increased muscle mass, preserved the survival of larger fibers, and decreased the expression of muscle-wasting effector genes. In a model of cancer cachexia, lithium chloride increased muscle mass, enhanced muscle strength, and increased fiber cross-sectional area, with no significant effect on tumor mass. These results indicate that lithium chloride exerts therapeutic effects on inflammation-mediated skeletal muscle wasting, such as sepsis-induced muscle atrophy and cancer cachexia.

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MMP12 Knockout Prevent Weight and Muscle Loss Induced by Cancer Cachexia

10.1101/2021.01.29.428838 ◽

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.

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The Pathway to Cancer Cachexia: MicroRNA-Regulated Networks in Muscle Wasting Based on Integrative Meta-Analysis

International Journal of Molecular Sciences ◽

10.3390/ijms20081962 ◽

2019 ◽

Vol 20 (8) ◽

pp. 1962 ◽

Cited By ~ 7

Author(s):

Paula Paccielli Freire ◽

Geysson Javier Fernandez ◽

Sarah Santiloni Cury ◽

Diogo de Moraes ◽

Jakeline Santos Oliveira ◽

...

Keyword(s):

Gene Expression ◽

Differentially Expressed Genes ◽

Muscle Atrophy ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Meta Analysis ◽

Therapeutic Strategies ◽

Expression Data ◽

Novel Therapeutic Strategies ◽

Novel Therapeutic

Cancer cachexia is a multifactorial syndrome that leads to significant weight loss. Cachexia affects 50%–80% of cancer patients, depending on the tumor type, and is associated with 20%–40% of cancer patient deaths. Besides the efforts to identify molecular mechanisms of skeletal muscle atrophy—a key feature in cancer cachexia—no effective therapy for the syndrome is currently available. MicroRNAs are regulators of gene expression, with therapeutic potential in several muscle wasting disorders. We performed a meta-analysis of previously published gene expression data to reveal new potential microRNA–mRNA networks associated with muscle atrophy in cancer cachexia. We retrieved 52 differentially expressed genes in nine studies of muscle tissue from patients and rodent models of cancer cachexia. Next, we predicted microRNAs targeting these differentially expressed genes. We also include global microRNA expression data surveyed in atrophying skeletal muscles from previous studies as background information. We identified deregulated genes involved in the regulation of apoptosis, muscle hypertrophy, catabolism, and acute phase response. We further predicted new microRNA–mRNA interactions, such as miR-27a/Foxo1, miR-27a/Mef2c, miR-27b/Cxcl12, miR-27b/Mef2c, miR-140/Cxcl12, miR-199a/Cav1, and miR-199a/Junb, which may contribute to muscle wasting in cancer cachexia. Finally, we found drugs targeting MSTN, CXCL12, and CAMK2B, which may be considered for the development of novel therapeutic strategies for cancer cachexia. Our study has broadened the knowledge of microRNA-regulated networks that are likely associated with muscle atrophy in cancer cachexia, pointing to their involvement as potential targets for novel therapeutic strategies.

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The Role of Autophagy Modulated by Exercise in Cancer Cachexia

Life ◽

10.3390/life11080781 ◽

2021 ◽

Vol 11 (8) ◽

pp. 781

Author(s):

Julia Windi Gunadi ◽

Ariyani Sudhamma Welliangan ◽

Ray Sebastian Soetadji ◽

Diana Krisanti Jasaputra ◽

Ronny Lesmana

Keyword(s):

Muscle Atrophy ◽

Muscle Function ◽

Cancer Cachexia ◽

Physiological Role ◽

Energy Utilization ◽

Patients With Cancer ◽

Different Types ◽

Exercise Type ◽

Type Of Exercise

Cancer cachexia is a syndrome experienced by many patients with cancer. Exercise can act as an autophagy modulator, and thus holds the potential to be used to treat cancer cachexia. Autophagy imbalance plays an important role in cancer cachexia, and is correlated to skeletal and cardiac muscle atrophy and energy-wasting in the liver. The molecular mechanism of autophagy modulation in different types of exercise has not yet been clearly defined. This review aims to elaborate on the role of exercise in modulating autophagy in cancer cachexia. We evaluated nine studies in the literature and found a potential correlation between the type of exercise and autophagy modulation. Combined exercise or aerobic exercise alone seems more beneficial than resistance exercise alone in cancer cachexia. Looking ahead, determining the physiological role of autophagy modulated by exercise will support the development of a new medical approach for treating cancer cachexia. In addition, the harmonization of the exercise type, intensity, and duration might play a key role in optimizing the autophagy levels to preserve muscle function and regulate energy utilization in the liver.

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Perturbed BMP signaling and denervation promote muscle wasting in cancer cachexia

Science Translational Medicine ◽

10.1126/scitranslmed.aay9592 ◽

2021 ◽

Vol 13 (605) ◽

pp. eaay9592

Author(s):

Roberta Sartori ◽

Adam Hagg ◽

Sandra Zampieri ◽

Andrea Armani ◽

Catherine E. Winbanks ◽

...

Keyword(s):

Skeletal Muscle ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Muscle Fibers ◽

Bmp Signaling ◽

Patients With Cancer ◽

Skeletal Muscle Wasting ◽

Morphogenetic Protein ◽

Motor Nerves ◽

Underlying Mechanisms

Most patients with advanced solid cancers exhibit features of cachexia, a debilitating syndrome characterized by progressive loss of skeletal muscle mass and strength. Because the underlying mechanisms of this multifactorial syndrome are incompletely defined, effective therapeutics have yet to be developed. Here, we show that diminished bone morphogenetic protein (BMP) signaling is observed early in the onset of skeletal muscle wasting associated with cancer cachexia in mouse models and in patients with cancer. Cancer-mediated factors including Activin A and IL-6 trigger the expression of the BMP inhibitor Noggin in muscle, which blocks the actions of BMPs on muscle fibers and motor nerves, subsequently causing disruption of the neuromuscular junction (NMJ), denervation, and muscle wasting. Increasing BMP signaling in the muscles of tumor-bearing mice by gene delivery or pharmacological means can prevent muscle wasting and preserve measures of NMJ function. The data identify perturbed BMP signaling and denervation of muscle fibers as important pathogenic mechanisms of muscle wasting associated with tumor growth. Collectively, these findings present interventions that promote BMP-mediated signaling as an attractive strategy to counteract the loss of functional musculature in patients with cancer.

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IGF-1 is downregulated in experimental cancer cachexia

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00104.2006 ◽

2006 ◽

Vol 291 (3) ◽

pp. R674-R683 ◽

Cited By ~ 99

Author(s):

Paola Costelli ◽

Maurizio Muscaritoli ◽

Maurizio Bossola ◽

Fabio Penna ◽

Patrizia Reffo ◽

...

Keyword(s):

Muscle Atrophy ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Signal Transduction Pathway ◽

Ubiquitin Proteasome System ◽

Underlying Mechanism ◽

Simple Relation ◽

Mrna Levels ◽

Experimental Conditions ◽

Skeletal Muscle Wasting

Cancer cachexia is characterized by skeletal muscle wasting that is mainly supported by hypercatabolism. Muscle atrophy has been suggested to depend on impaired IGF-1 signal transduction pathway. The present study has been aimed at investigating the IGF-1 system in rats bearing the AH-130 hepatoma, a well-characterized model of cachexia. IGF-1 mRNA expression in the gastrocnemius of tumor hosts progressively decreases to ∼50% of controls. By contrast, both IGF-1 receptor and insulin receptor mRNA levels increase in day 7 AH-130 hosts. IGF-1 and insulin circulating levels, as well as IGF-1 expression in the liver, are reduced. Muscle wasting in the AH-130 bearers is associated with hyperactivation of the ubiquitin-proteasome system. Consistently, the mRNA levels of ubiquitin and of the ubiquitin ligases atrogin-1 and MuRF1 are significantly increased in the gastrocnemius of day 7 AH-130 hosts. Exogenous IGF-1 administered to tumor bearers does not prevent cachexia. IGF-1 mRNA levels also have been evaluated in the gastrocnemius of AH-130 hosts treated with pentoxifylline, an inhibitor of TNF-α synthesis, alone or combined with formoterol, a β2-adrenergic agonist. Both treatments partially correct muscle atrophy without modifying IGF-1 and atrogin-1 mRNA levels, whereas MuRF1 hyperexpression is reduced by the combination of pentoxifylline with formoterol. These results demonstrate for the first time that the IGF-1 system is downregulated in cancer cachexia, although the underlying mechanism remains unknown. Moreover, no simple relation linking IGF-1 and/or atrogin-1 mRNA levels and muscle atrophy could be observed in these experimental conditions. Further studies are thus needed to clarify both issues.

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