PGAM5 interacts with and maintains BNIP3 to license cancer-associated muscle wasting
Qingyuan ZhangChunhui ChenYe MaXinyi YanNianhong LaiHao WangBaogui GaoAnna Meilin GuQinrui HanQingling ZhangLei LaXuegang Sun
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Abstract:
Regressing the accelerated degradation of skeletal muscle protein is a significant goal for cancer cachexia management. Here, we show that genetic deletion of Pgam5 ameliorates skeletal muscle atrophy in various tumor-bearing mice. pgam5 ablation represses excessive myoblast mitophagy and effectively suppresses mitochondria meltdown and muscle wastage. Next, we define BNIP3 as a mitophagy receptor constitutively associating with PGAM5. bnip3 deletion restricts body weight loss and enhances the gastrocnemius mass index in the age- and tumor size-matched experiments. The NH2-terminal region of PGAM5 binds to the PEST motif-containing region of BNIP3 to dampen the ubiquitination and degradation of BNIP3 to maintain continuous mitophagy. Finally, we identify S100A9 as a pro-cachectic chemokine via activating AGER/RAGE. AGER deficiency or S100A9 inhibition restrains skeletal muscle loss by weakening the interaction between PGAM5 and BNIP3. In conclusion, the AGER-PGAM5-BNIP3 axis is a novel but common pathway in cancer-associated muscle wasting that can be targetable. Abbreviation: AGER/RAGE: advanced glycation end-product specific receptor; BA1: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; Ckm-Cre: creatinine kinase, muscle-specific Cre; CM: conditioned medium; CON/CTRL: control; CRC: colorectal cancer; FUNDC1: FUN14 domain containing 1; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; S100A9: S100 calcium binding protein A9; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23; TSKO: tissue-specific knockout; VDAC1: voltage dependent anion channel 1.Keywords:
Cancer Cachexia
Protein Degradation
Muscle wasting is an extremely common feature of several chronic diseases associated with inflammatory activation. It can be part of a wasting syndrome known as cachexia 1, 2. The defining feature of cachexia is overt weight loss, but muscle wasting can also become prevalent without weight loss being detectable. This notion is important, because it highlights the necessity to not only measure weight, but also to assess strength as well as functional and exercise capacity in patients with advanced chronic disease, but also in healthy elderly subjects 3, 4. Relevant illnesses include, for example, chronic heart failure 5, chronic kidney disease 6, chronic obstructive pulmonary disease 7, rheumatoid arthritis 8, and cancer 9. Considering these conditions alone, it has been estimated that the number of patients at risk of developing cachexia is 17.5 million in Europe, whereas the number of patients actually being cachectic is close to 4 million 10. Muscle wasting can be diagnosed, but it is more easily overlooked. Screening measures include the assessment of handgrip strength, the 6-minute corridor walk test, or simple tools such as the short physical performance battery test. All of these are easily performed and take 30 s to no more than 10 min. However, the chances for the patient to actively complain about loss of strength are relatively low, and many elderly subjects consider loss of strength part of the normal ageing process rather than part of advancing disease. Measures to tackle the loss of muscle and strength and, thus, quality of life include nutritional interventions, exercise and, possibly, pharmacotherapy 11-13. The most promising drug classes in this regard that have seen research endeavour in recent years include myostatin inhibitors, ghrelin receptor agonists, selective androgen receptor modulators and anabolic steroids such as testosterone. Testosterone was originally described by Kàroly David and colleagues in 1935 14. Its primary site of synthesis are the Leydig cells of the testis, and smaller amounts are released from the adrenal cortex and the ovaries. Therefore, plasma levels of testosterone in men are 10 times higher than those in women 15. Testosterone became available for therapeutic use as an injectable drug in the 1940s. In the 1970s, an orally available formulation was approved. Testosterone is metabolized to dihydrotestosterone and estradiol, both of which have feedback effects on luteinizing hormone secretion. This point is worth stressing, because some of the undesired effects of testosterone may be due to the formation of metabolites, rather than due to the effects of testosterone itself. Since steroid receptors just like the androgen receptor are expressed close to ubiquitously in humans, their blockade or activation can be associated with untoward effects. For example, supraphysiological testosterone levels have been associated with acne, dyslipidaemia, sleep apnoea, left ventricular hypertrophy, sodium and water retention, increases in renin-angiotensin-aldosterone system activity and blood pressure as well as increases in erythropoiesis 15-17. In addition, testosterone administration has been associated with increased cardiovascular mortality, prostate cancer and hepatic toxicity 15, 18, 19. On the other hand, testosterone can induce bone and muscle growth ultimately leading to increases in strength 20. Side effects of testosterone have mainly been described in patients who abuse the drug. In clinical settings, adverse effects have generally been mild and reversible 15. The mixture of desired and undesired effects is present in all steroids; however, it led to the idea of developing selective steroid receptor modulators (Figure 1) 21. The best known example in clinical use in this regard is tamoxifen, which functions as an oestrogen receptor antagonist in the breast and as an agonist in the uterus. Such selective receptor modulators have been in clinical development also as selective glucocorticoid receptor modulators, selective progesterone receptor modulators and selective androgen receptor modulators 21. In a recent issue of BJCP, Clark and colleagues present a Phase I study of a novel selective androgen receptor modulator (SARM) named GSK2881078 22. With the European Medicines Agency's (EMA) rejection of the application for marketing authorization of anamorelin, a ghrelin receptor agonist, in May 2017 23, this class of drugs merits further scrutiny (Figure 1). Indeed, GSK2881078 adds to the list of SARMs in clinical development that include substances like DT-100, enobosarm, ligandrol and MK-0773 24. The only one of these to see Phase III testing is enobosarm; however, its development was unfortunately discontinued 25. Therefore, this new piece in the SARM puzzle comes as a welcome addition. On the other hand, it appears that all drugs that aim at treating muscle wasting struggle with the same problem: to improve both muscle mass and muscle function at the same time. Even though the two – muscle mass and muscle function – appear almost automatically linked, this has not been the case in the two major trials of anamorelin 26 and only partially in the two trials of enobosarm 27, 28. In fact, these trials have shown significant improvements in muscle mass, but the increase in strength or functional capacity has been less convincing. Pharmacokinetic data of the new SARM GSK2881078 showed a rapid initial absorption and a long half-life of more than 100 h with slightly higher values in women than men. Pharmacodynamics showed reductions in the serum levels of testosterone, dihydrotestosterone and sex-hormone binding globulin relative to baseline. Overall safety was acceptable. In summary, no major surprises were revealed during Phase I testing, and the data may prompt testing in Phase II. Whatever endpoint the investigators may want to choose in a Phase II study, it should include testing of muscle function using easily applicable tests such as the 6-minute walk test, the stair-climbing power test, the short physical performance battery test or at least handgrip strength. Selecting the right patient population for such a study is another major challenge: patients with cancer cachexia, particularly in cancers of the lung or the pancreas, may simply be too sick to benefit from pharmacological treatment of muscle wasting. It may be worth selecting patients at an earlier stage such as in pre-cachexia or sarcopenia with the aim of maintaining (rather than improving) muscle mass and function. Such questions are so important that regulators at the EMA or the Food and Drug Administration are requested to provide even more guidance in what they expect to achieve in a clinical trial of muscle wasting 29. S.v.H. has received consultant honoraria from Vifor Pharma, Chugai, Helsinn, Novartis, Pfizer and Boheringer Ingelheim.
Wasting Syndrome
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Cachexia, weight loss, and muscular wasting are characteristics of advanced infection with the human immunodeficiency virus (HIV). Death usually occurs when 20% of total body weight is lost. Usually, when an individual develops this syndrome, commonly known as AIDS wasting, it is a poor prognostic sign for survival. The impact of modern treatments for AIDS infections with antiretroviral drugs and protease inhibitors has had a positive impact to increase long-term survival with the disease. AIDS wasting is now becoming much less common The pathogenesis of AIDS wasting involves poor appetite, inefficient use of caloric intake because of intercurrent diseases, medication-induced gastrointestinal problems (nausea, vomiting, and diarrhea), and the effect of HIV infection itself on muscle and tissue breakdown (1,2).
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Abstract Muscle wasting is common and persistent in severely burned patients, worsened by immobilization during treatment. In this review, we posit two major phenotypes of muscle wasting after severe burn, cachexia and sarcopenia, each with distinguishing characteristics to result in muscle atrophy; these characteristics are also likely present in other critically ill populations. An online search was conducted from the PubMed database and other available online resources and we manually extracted published articles in a systematic mini review. We describe the current definitions and characteristics of cachexia and sarcopenia and relate these to muscle wasting after severe burn. We then discuss these putative mechanisms of muscle atrophy in this condition. Severe burn and immobilization have distinctive patterns in mediating muscle wasting and muscle atrophy. In considering these two pathological phenotypes (cachexia and sarcopenia), we propose two independent principal causes and mechanisms of muscle mass loss after burns: (1) inflammation‐induced cachexia, leading to proteolysis and protein degradation, and (2) sarcopenia/immobility that signals inhibition of expected increases in protein synthesis in response to protein loss. Because both are present following severe burn, these should be considered independently in devising treatments. Discussing cachexia and sarcopenia as independent mechanisms of severe burn–initiated muscle wasting is explored. Recognition of these associated mechanisms will likely improve outcomes.
Muscle Atrophy
Wasting Syndrome
Protein Degradation
Myostatin
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Abstract: Cachexia and muscle wasting are frequently observed in heart failure patients. Cachexia is a predictor of reduced survival, independent of important parameters such as age, heart failure functional class, and functional capacity. Muscle and fat wasting can also predict adverse outcome during cardiac failure. Only more recently were these conditions defined in International Consensus. Considering that heart failure is an inflammatory disease, cardiac cachexia has been diagnosed by finding a body weight loss >5%, in the absence of other diseases and independent of other criteria. Muscle wasting has been defined as lean appendicular mass corrected for height squared of 2 standard deviations or more below the mean for healthy individuals between 20 years and 30 years old from the same ethnic group. The etiology of heart failure-associated cachexia and muscle wasting is multifactorial, and the underlying physiopathological mechanisms are not completely understood. The most important factors are reduced food intake, gastrointestinal alterations, immunological activation, neurohormonal abnormalities, and an imbalance between anabolic and catabolic processes. Cachexia and muscle wasting have clinical consequences in several organs and systems including the gastrointestinal and erythropoietic systems, and the heart, previously affected by the primary disease. We hope that a better understanding of the mechanisms involved in their physiopathology will allow the development of pharmacological and nonpharmacological therapies to effectively prevent and treat heart failure-induced cachexia and muscle wasting before significant body weight and muscle wasting occurs. Keywords: heart failure, prognosis, anorexia, inflammatory activation, cardiac wasting
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Wasting can present in different forms in patients with chronic illness. Whilst cachexia can be easily diagnosed using weighing scales, the diagnosis of sarcopenia, i.e. loss of skeletal muscle mass and strength, requires more sophisticated technologies. Indeed, sarcopenia and cachexia are different clinical entities. In patients with heart failure or chronic obstructive pulmonary disease (COPD), both have been well recognized as common and partly reversible features that have tremendous effects on patients exercise capacity, quality of life and on survival. Therapeutic approaches may require a combined approach embracing exercise training, nutritional counselling, and drug therapy.
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This article highlights pre-clinical and clinical studies into the field of wasting disorders that were presented at the 8th Cachexia Conference held in Paris, France December 2015. This year some interesting results of clinical trials and different new therapeutic targets were shown. This article presents the biological and clinical significance of different markers and new drugs for the treatment of skeletal muscle wasting. Effective treatments of cachexia and wasting disorders are urgently needed in order to improve the patients' quality of life and their survival.
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Cachexia is a complex metabolic syndrome characterised by severe weight loss due largely to skeletal muscle wasting. It correlates with poor survival times and a decreased quality of life. Although most cancer patients develop cachexia at some point during their illness, the condition is seldom given the recognition it deserves by healthcare staff
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Interleukin 6 (IL-6) has received significant attention for its regulatory role in muscle wasting during cachexia. This review examines the role of circulating IL-6 for decreasing muscle mass during cancer and emphasizes some of the indirect actions of IL-6 that may cause muscle wasting.
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