Perturbed BMP signaling and denervation promote muscle wasting in cancer cachexia

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.

scholarly journals Understanding the common mechanisms of heart and skeletal muscle wasting in cancer cachexia

Oncogenesis ◽  
2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Valentina Rausch ◽  
Valentina Sala ◽  
Fabio Penna ◽  
Paolo Ettore Porporato ◽  
Alessandra Ghigo
Keyword(s):  
Skeletal Muscle ◽  
Cancer Cachexia ◽  
Total Body Weight ◽  
Cardiovascular Complications ◽  
Patients With Cancer ◽  
Skeletal Muscle Wasting ◽  
Cardiac Muscles ◽  
Total Body ◽  
Underlying Mechanisms ◽  
Effective Treatments

AbstractCachexia is a severe complication of cancer that adversely affects the course of the disease, with currently no effective treatments. It is characterized by a progressive atrophy of skeletal muscle and adipose tissue, resulting in weight loss, a reduced quality of life, and a shortened life expectancy. Although the cachectic condition primarily affects the skeletal muscle, a tissue that accounts for ~40% of total body weight, cachexia is considered a multi-organ disease that involves different tissues and organs, among which the cardiac muscle stands out for its relevance. Patients with cancer often experience severe cardiac abnormalities and manifest symptoms that are indicative of chronic heart failure, including fatigue, shortness of breath, and impaired exercise tolerance. Furthermore, cardiovascular complications are among the major causes of death in cancer patients who experienced cachexia. The lack of effective treatments for cancer cachexia underscores the need to improve our understanding of the underlying mechanisms. Increasing evidence links the wasting of the cardiac and skeletal muscles to metabolic alterations, primarily increased energy expenditure, and to increased proteolysis, ensuing from activation of the major proteolytic machineries of the cell, including ubiquitin-dependent proteolysis and autophagy. This review aims at providing an overview of the key mechanisms of cancer cachexia, with a major focus on those that are shared by the skeletal and cardiac muscles.

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

2018 ◽  
Vol 3 (2) ◽  
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. 

scholarly journals Exercise as an anti-inflammatory therapy for cancer cachexia: a focus on interleukin-6 regulation

2020 ◽  
Vol 318 (2) ◽  
pp. R296-R310 ◽  
Author(s):  
Hélène N. Daou
Keyword(s):  
Skeletal Muscle ◽  
Systemic Inflammation ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Skeletal Muscle Atrophy ◽  
Ampk Signaling ◽  
Skeletal Muscle Wasting ◽  
Skeletal Muscle Loss ◽  
Anti Inflammatory ◽  
Tumor Growth And Metastasis

Cancer cachexia is a complicated disorder of extreme, progressive skeletal muscle wasting. It is directed by metabolic alterations and systemic inflammation dysregulation. Numerous studies have demonstrated that increased systemic inflammation promotes this type of cachexia and have suggested that cytokines are implicated in the skeletal muscle loss. Exercise is firmly established as an anti-inflammatory therapy that can attenuate or even reverse the process of muscle wasting in cancer cachexia. The interleukin IL-6 is generally considered to be a key player in the development of the microenvironment of malignancy; it promotes tumor growth and metastasis by acting as a bridge between chronic inflammation and cancerous tissue and it also induces skeletal muscle atrophy and protein breakdown. Paradoxically, a beneficial role for IL-6 has also been identified recently, and that is its status as a “founding member” of the myokine class of proteins. Skeletal muscle is an important source of circulating IL-6 in people who participate in exercise training. IL-6 acts as an anti-inflammatory myokine by inhibiting TNFα and improving glucose uptake through the stimulation of AMPK signaling. This review discusses the action of IL-6 in skeletal muscle tissue dysfunction and the role of IL-6 as an “exercise factor” that modulates the immune system. This review also sheds light on the main considerations related to the treatment of muscle wasting in cancer cachexia.

scholarly journals The Adipokines in Cancer Cachexia

2020 ◽  
Vol 21 (14) ◽  
pp. 4860 ◽  
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.

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 The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass

2013 ◽  
Vol 203 (2) ◽  
pp. 345-357 ◽  
Author(s):  
Catherine E. Winbanks ◽  
Justin L. Chen ◽  
Hongwei Qian ◽  
Yingying Liu ◽  
Bianca C. Bernardo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Bmp Signaling ◽  
Positive Regulator ◽  
Bmp Receptors ◽  
Morphogenetic Protein

Although the canonical transforming growth factor β signaling pathway represses skeletal muscle growth and promotes muscle wasting, a role in muscle for the parallel bone morphogenetic protein (BMP) signaling pathway has not been defined. We report, for the first time, that the BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling. In agreement, we observed that BMP signaling is augmented in models of muscle growth. Importantly, stimulation of BMP signaling is essential for conservation of muscle mass after disruption of the neuromuscular junction. Inhibiting the phosphorylation of Smad1/5 exacerbated denervation-induced muscle atrophy via an HDAC4-myogenin–dependent process, whereas increased BMP–Smad1/5 activity protected muscles from denervation-induced wasting. Our studies highlight a novel role for the BMP signaling pathway in promoting muscle growth and inhibiting muscle wasting, which may have significant implications for the development of therapeutics for neuromuscular disorders.

scholarly journals Mitofusin-2 prevents skeletal muscle wasting in cancer cachexia

2016 ◽  
Vol 12 (5) ◽  
pp. 4013-4020 ◽  
Author(s):  
Qiu-Lei Xi ◽  
Bo Zhang ◽  
Yi Jiang ◽  
Hai-Sheng Zhang ◽  
Qing-Yang Meng ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Mitofusin 2 ◽  
Skeletal Muscle Wasting

scholarly journals Myostatin is a novel tumoral factor that induces cancer cachexia

2012 ◽  
Vol 446 (1) ◽  
pp. 23-36 ◽  
Author(s):  
Sudarsanareddy Lokireddy ◽  
Isuru Wijerupage Wijesoma ◽  
Sabeera Bonala ◽  
Meng Wei ◽  
Siu Kwan Sze ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Skeletal Muscles ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Transforming Growth Factor ◽  
C2c12 Myotubes ◽  
E3 Ligases ◽  
Molecular Features ◽  
Skeletal Muscle Wasting

Humoral and tumoral factors collectively promote cancer-induced skeletal muscle wasting by increasing protein degradation. Although several humoral proteins, namely TNFα (tumour necrosis factor α) and IL (interleukin)-6, have been shown to induce skeletal muscle wasting, there is a lack of information regarding the tumoral factors that contribute to the atrophy of muscle during cancer cachexia. Therefore, in the present study, we have characterized the secretome of C26 colon cancer cells to identify the tumoral factors involved in cancer-induced skeletal muscle wasting. In the present study, we show that myostatin, a procachectic TGFβ (transforming growth factor β) superfamily member, is abundantly secreted by C26 cells. Consistent with myostatin signalling during cachexia, treating differentiated C2C12 myotubes with C26 CM (conditioned medium) resulted in myotubular atrophy due to the up-regulation of muscle-specific E3 ligases, atrogin-1 and MuRF1 (muscle RING-finger protein 1), and enhanced activity of the ubiquitin–proteasome pathway. Furthermore, the C26 CM also activated ActRIIB (activin receptor type II B)/Smad and NF-κB (nuclear factor κB) signalling, and reduced the activity of the IGF-I (insulin-like growth factor 1)/PI3K (phosphoinositide 3-kinase)/Akt pathway, three salient molecular features of myostatin action in skeletal muscles. Antagonists to myostatin prevented C26 CM-induced wasting in muscle cell cultures, further confirming that tumoral myostatin may be a key contributor in the pathogenesis of cancer cachexia. Finally, we show that treatment with C26 CM induced the autophagy–lysosome pathway and reduced the number of mitochondria in myotubes. These two previously unreported observations were recapitulated in skeletal muscles collected from C26 tumour-bearing mice.

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