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 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 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 Methylarginine metabolites are associated with attenuated muscle protein synthesis in cancer-associated muscle wasting

2020 ◽  
Vol 295 (51) ◽  
pp. 17441-17459
Author(s):  
Hawley E. Kunz ◽  
Jessica M. Dorschner ◽  
Taylor E. Berent ◽  
Thomas Meyer ◽  
Xuewei Wang ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Muscle Mass ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mitochondrial Protein ◽  
Coupling Efficiency ◽  
C2c12 Myotubes ◽  
Tumor Bearing

Cancer cachexia is characterized by reductions in peripheral lean muscle mass. Prior studies have primarily focused on increased protein breakdown as the driver of cancer-associated muscle wasting. Therapeutic interventions targeting catabolic pathways have, however, largely failed to preserve muscle mass in cachexia, suggesting that other mechanisms might be involved. In pursuit of novel pathways, we used untargeted metabolomics to search for metabolite signatures that may be linked with muscle atrophy. We injected 7-week–old C57/BL6 mice with LLC1 tumor cells or vehicle. After 21 days, tumor-bearing mice exhibited reduced body and muscle mass and impaired grip strength compared with controls, which was accompanied by lower synthesis rates of mixed muscle protein and the myofibrillar and sarcoplasmic muscle fractions. Reductions in protein synthesis were accompanied by mitochondrial enlargement and reduced coupling efficiency in tumor-bearing mice. To generate mechanistic insights into impaired protein synthesis, we performed untargeted metabolomic analyses of plasma and muscle and found increased concentrations of two methylarginines, asymmetric dimethylarginine (ADMA) and NG-monomethyl-l-arginine, in tumor-bearing mice compared with control mice. Compared with healthy controls, human cancer patients were also found to have higher levels of ADMA in the skeletal muscle. Treatment of C2C12 myotubes with ADMA impaired protein synthesis and reduced mitochondrial protein quality. These results suggest that increased levels of ADMA and mitochondrial changes may contribute to impaired muscle protein synthesis in cancer cachexia and could point to novel therapeutic targets by which to mitigate cancer cachexia.

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.

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 The Toll-Like Receptor/MyD88/XBP1 Signaling Axis Mediates Skeletal Muscle Wasting during Cancer Cachexia

2019 ◽  
Vol 39 (15) ◽  
Author(s):  
Kyle R. Bohnert ◽  
Praneeth Goli ◽  
Anirban Roy ◽  
Aditya K. Sharma ◽  
Guangyan Xiong ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Active Form ◽  
Primary Response ◽  
Downstream Target ◽  
Tumor Bearing ◽  
Skeletal Muscle Wasting

ABSTRACT Skeletal muscle wasting causes both morbidity and mortality of cancer patients. Accumulating evidence suggests that the markers of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathways are increased in skeletal muscle under multiple catabolic conditions, including cancer. However, the signaling mechanisms and the role of individual arms of the UPR in the regulation of skeletal muscle mass remain largely unknown. In the present study, we demonstrated that gene expression of Toll-like receptors (TLRs) and myeloid differentiation primary response gene 88 (MyD88) was increased in skeletal muscle in a Lewis lung carcinoma (LLC) model of cancer cachexia. Targeted ablation of MyD88 inhibits the loss of skeletal muscle mass and strength in LLC tumor-bearing mice. Inhibition of MyD88 attenuates the LLC-induced activation of the UPR in skeletal muscle of mice. Moreover, muscle-specific deletion of X-box binding protein 1 (XBP1), a major downstream target of IRE1α arm of the UPR, ameliorates muscle wasting in LLC tumor-bearing mice. Our results also demonstrate that overexpression of an active form of XBP1 caused atrophy in cultured myotubes. In contrast, knockdown of XBP1 inhibits myotube atrophy in response to LLC or C26 adenocarcinoma cell conditioned medium. Collectively, our results demonstrate that TLR/MyD88-mediated activation of XBP1 causes skeletal muscle wasting in LLC tumor-bearing mice.

scholarly journals A Combination of Formoterol and the Histone Deacetylase Inhibitor AR42 has No Effects on Muscle Mass in Tumor-Bearing Rats

2021 ◽  
pp. 1-6
Author(s):  
Silvia Busquets ◽  
Marta Castillejo ◽  
Queralt Jove ◽  
Alina Noguera ◽  
Francisco J. López-Soriano ◽  
...  
Keyword(s):  
Body Weight ◽  
Olive Oil ◽  
Histone Deacetylase ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Body Weight Loss ◽  
Tissue Loss ◽  
Tumor Bearing ◽  
Deacetylase Inhibitor ◽  
Β2 Agonists

Background: Accelerated muscle and adipose tissue loss are two of the main aspects of cancer cachexia. β2-agonists seem to be successful in the treatment of cachexia in experimental animals. The aim if the present investigation was to study the effects on body weight loss in tumor-bearing animals of a combination of formoterol and AR-42, an inhibitor of histone deacetylase (HDAC). Methods: Rats were divided into two groups, namely controls (C) and tumor-bearing (T). TB group was further divided into four subgroups: untreated (saline as a vehicle), treated with Formoterol (F) (0,3 mg/kg body weight in saline, subcutaneous (s.c.), daily), treated with AR-42 (A) (20 mg/kg body weight in olive oil, intragastric (i.g.), only the last 4 days). and double-treated treated (TFA) with Formoterol (0,3 mg/kg body weight, subcutaneous (s.c.), daily) and AR-42 (20 mg/kg body weight in olive oil, intragastric (i.g.), only the last 4 days). 7 days after tumor transplantation, muscle weights, grip force and total physical activity were determined in all experimental groups. Results: The presence of the Yoshida AH-130 ascites hepatoma induced severe muscle wasting in rats. Treatment of the tumor-bearing animals with the beta2-agonist formoterol (0,3 mg/kg), resulted in a significant improvement in the cachectic state of the animals. Treatment of the tumor-bearing animals with AR42 did not result in any effects on muscle wasting in the cachectic rats. Furthermore, the combination of formoterol and AR42 showed no additional effects to those observed with just formoterol. Conclusion: The results presented question the previously described effects of AR42 on cancer cachexia, probably due to its effect on tumor growth.

Inhibition of HSP90 reverses STAT3‐mediated muscle wasting in cancer cachexia mice

2021 ◽  
Author(s):  
Mengyuan Niu ◽  
Shiyu Song ◽  
Zhonglan Su ◽  
Lulu Wei ◽  
Li Li ◽  
...  
Keyword(s):  
Cancer Cachexia ◽  
Muscle Wasting
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