Masakazu Saitoh

Sarcopenia, cachexia, and muscle performance in heart failure: Review update 2016

Cachexia in the context of heart failure (HF) has been termed cardiac cachexia, and represents a progressive involuntary weight loss. Cachexia is mainly the result of an imbalance in the homeostasis of muscle protein synthesis and degradation due to a lower activity of protein synthesis pathways and an over-activation of protein degradation. In addition, muscle wasting leads to of impaired functional capacity, even after adjusting for clinical relevant variables in patients with HF. However, there is no sufficient therapeutic strategy in muscle wasting in HF patients and very few studies in animal models. Exercise training represents a promising intervention that can prevent or even reverse the process of muscle wasting, and worsening the muscle function and performance in HF with muscle wasting and cachexia. The pathological mechanisms and effective therapeutic approach of cardiac cachexia remain uncertain, because of the difficulty to establish animal cardiac cachexia models, thus novel animal models are warranted. Furthermore, the use of improved animal models will lead to a better understanding of the pathways that modulate muscle wasting and therapeutics of muscle wasting of cardiac cachexia.

Myostatin signaling is up-regulated in female patients with advanced heart failure

BACKGROUND Myostatin, a negative regulator of skeletal muscle mass, is up-regulated in the myocardium of heart failure (HF) and increased myostatin is associated with weight loss in animal models with HF. Although there are disparities in pathophysiology and epidemiology between male and female patients with HF, it remains unclear whether there is gender difference in myostatin expression and whether it is associated with weight loss in HF patients. METHODS Heart tissue samples were collected from patients with advanced heart failure (n=31, female n=5) as well as healthy control donors (n=14, female n=6). Expression levels of myostatin and its related proteins in the heart were evaluated by western blotting analysis. RESULTS Body mass index was significantly lower in female HF patients than in male counterparts (20.0±4.2 in female vs 25.2±3.8 in male, p=0.04). In female HF patients, both mature myostatin and pSmad2 were significantly up-regulated by 1.9 fold (p=0.05) and 2.5 fold (p<0.01) respectively compared to female donors, while expression of pSmad2 was increased by 2.8 times in male HF patients compared to male healthy subjects, but that of myostatin was not. There was no significant difference in protein expression related to myostatin signaling between male and female patients. CONCLUSION In this study, myostatin and pSmad2 were significantly up-regulated in the failing heart of female patients, but not male patients, and female patients displayed lower body mass index. Enhanced myostatin signaling in female failing heart may causally contribute to pathogenesis of HF and cardiac cachexia.

Anorexia, functional capacity, and clinical outcome in patients with chronic heart failure: results from the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF)

We aimed to assess determinants of anorexia, that is loss of appetite in patients with heart failure (HF) and aimed to further elucidate the association between anorexia, functional capacity, and outcomes in affected patients.

Muscle wasting in heart failure : The role of nutrition.

SummaryMuscle wasting and malnutrition are common complications in patients with advanced heart failure (HF); however, both remain underdiagnosed and undertreated although they both play relevant roles in the progression of HF. The risk of muscle wasting in patients with HF increases in those patients with malnutrition or at risk of malnutrition. Muscle wasting and malnutrition are thought to be positively influenced by adequate therapeutic interventions such as physical activity and nutritional support. Consequently, early detection of malnutrition in patients with HF is recommended. This review discusses muscle wasting and nutritional status, describing the effects of malnutrition on muscle wasting in patients with HF. We review specific issues related to muscle wasting and nutritional status in patients with HF; however, no established strategies currently exist to focus on patients suffering from muscle wasting with malnutrition.

The concept that focuses on oral motor and feeding function in cancer patients with muscle wasting: Skeletal muscle mass is associated with severe dysphagia in cancer patients.

I read with great interest the recent article reporting the relation between skeletal muscle mass and dysphagia in cancer patients by Hidetaka Wakabayashi et al.1 In criteria for the diagnosis of sarcopenia, loss of muscle mass, reduced handgrip strength, or gait speed is assessed as representative value of impaired muscle strength or physical performance.2, 3 Assessment of oral motor and feeding function is not common in diagnostic testing for sarcopenia or cachexia; however; loss of muscle mass is supposed to be spread throughout the entire body. Insufficient dietary intake and decreased appetite are major factors for loss of muscle mass.4 Therefore, increasing dietary intake and appetite could be one of the treatments for improvement of muscle wasting. However, some complications of cancer or chemotherapy often interfere with appetite, oral motor and feeding function in cancer patients.5, 6 Loss of muscle mass and impaired physical performance, and activity of daily living (ADL) induced by cancer and chemotherapy cannot be fully reversed by conventional nutritional support alone.7, 8 These clinical trials support the hypothesis that nutritional support would not be enough for strategy in advanced cancer patients with of oral motor and feeding dysfunction. In order to make a better understanding the strategy of cancer patients with sarcopenia or cachexia, evaluation of the oral motor and feeding function is no less important than assessment of dietary habit or nutritional status according to biochemical, anthropometric measures, and nutritional screening tool. It remains unclear whether hybrid strategy combining both nutritional support and exercise or rehabilitation affected on the loss of muscle mass, impaired ADL, and quality of life in cancer patients with dysphagia accompanied by sarcopenia or cachexia.4, 9 Further advances are required.

Growth differentiation factor‐15 as a prognostic biomarker in cancer patients

Growth differentiation factor‐15 (GDF15) is a member of the transforming growth factor beta superfamily and has been demonstrated to play multiple roles in various pathological conditions such as cancer, inflammatory diseases, cardiovascular diseases, and metabolic disorders.1 Furthermore, recent studies have shown that plasma levels of GDF15 increased in patients with chronic diseases described previously1 and that elevated GDF15 was associated with poor prognosis in patients with malignancy such as prostate cancer and upper gastrointestinal cancer.2, 3 In this study, Lerner et al. reported that elevated plasma GDF15 levels are associated with increased cancer‐related weight loss and decreased survival in cancer male patients.4 Cancer‐related weight loss has been shown to be an independent predictor for survival in cancer patients,5 which suggests that treatment for cancer cachexia might lead to the better outcome in cancer patients with weight loss. Recent studies have found several diagnostic biomarkers for loss of muscle mass such as N‐terminal peptide of procollagen type III, C‐terminal agrin fragment, leptin, ghrelin, and obestatin6, 7 and prognostic biomarkers in cancer patients such as matrix metalloproteinases, survivin, and butyrylcholinesterase.8, 9, 10 Although GDF15 might also be a useful prognostic marker in cancer patients, the small sample size, the heterogeneous population, and the selection bias could have some impacts on the findings in this study. To clarify the pathophysiological significance of GDF15 in cancer patients, validation studies on larger sample size including various cancer types and different pathological stages are needed. In addition, further research should demonstrate which biomarker including GDF15 and other novel biomarkers shows better diagnostic or prognostic performance or whether a multi‐marker approach is superior to each biomarker. Finally, it is of great research interest and clinical value whether these biomarkers could be the cancer therapeutic targets in this population.

Clinical perspective for wasting in diaphragm, an ever‐trained muscle

Dear Editor, We read with great interest the recent article comparing the mechanisms under muscle wasting in quadriceps and diaphragm using an animal model by Mangner et al. While muscle wasting in heart failure (HF) patients is associated with poor exercise capacity and prognosis, current clinical evidences in therapeutic approach have been limited to ones by exercise training. As the author referred in their introduction, however, the function in diaphragm may be impaired in HF even though HF may induce ‘training-like’ benefit on diaphragm. This notion suggests that there may be some possible mechanisms other than deconditioning under wasting in diaphragm, and the results in this article would be one of them, namely, lack of elevation in oxidative enzyme activity in diaphragm. Besides, malnutrition may disrupt the effect of exercise training, and anabolic hormone may be insufficient in some patients. In a recent clinical research, the prognostic impact of respiratory muscle wasting was not consistent with the results from studies in 1990s, suggesting heterogeneity in the significance of respiratory muscle wasting in HF patients, which may not have been observed in animals. In limb muscle on the other hand, deconditioning may prevalently exist under wasting and attenuate the heterogeneity in the prognostic significance of wasting. Taken together, much more evidence will be needed until we can estimate if respiratory muscle wasting would be an important therapeutic target in HF patients.

Neuromuscular electrical stimulation for muscle wasting in heart failure patients

Neuromuscular electrical stimulation (NMES) seems to be safe and beneficial in improvement in functional capacity, muscle strength, and quality of life when compared with conventional aerobic exercise, while the change in muscle fiber composition and muscle size was conflicting in patients with heart failure (HF). Moreover, NMES studies seem to have beneficial effects on pro-inflammatory cytokine, oxidative enzyme activity, and protein anabolic and catabolic metabolism that are the key molecular mechanism of muscle wasting in patients with HF. We review specific issues related to the effects of NMES on muscle wasting in patients with HF, whether NMES seems to be an alternative exercise modality preventing or improving in muscle wasting for HF patients who are unable or unwilling to engage in conventional exercise training; however no established strategies currently exist to focus on the patients with HF accompanied by muscle wasting.

Myostatin inhibitors as pharmacological treatment for muscle wasting and muscular dystrophy

Myostatin, a member of the transforming growth factor beta (TGF‐β) superfamily that is highly expressed in skeletal muscle, was first described in 1997. It has been known that loss of myostatin function induces an increase in muscle mass in mice, cow, dogs and humans. Therefore, myostatin and its receptor have emerged as a therapeutic target for loss of skeletal muscle such as sarcopenia and cachexia, as well as muscular dystrophies. At the molecular level, myostatin binds to and activates the activin receptor IIB (ActRIIB)/Alk 4/5 complex. Therapeutic approaches therefore are being taken both pre‐clinically and clinically to inhibit the myostatin signaling pathway. Several myostatin inhibitors, including myostatin antibodies, anti‐myostatin peptibody, activin A antibody, soluble (decoy) forms of ActRIIB (ActR II B‐Fc), anti‐myostatin adnectin, ActR II B antibody have been tested in the last decade. The aim of this review is to present the current knowledge of several myostatin inhibitors as a therapeutic approach for patients with loss of skeletal muscle.

Is cardiac wasting accompanied by skeletal muscle loss in breast cancer patients receiving anticancer treatment

We have read with great interest the article by Klassen et al., which demonstrated that muscle strength was significantly decreased in breast cancer patients receiving anticancer treatment, compared with healthy subjects. In addition to impaired muscle strength, chemotherapyinduced cardiomyopathy has drawn much attention in this field. Intriguingly, some patients have shown dose-independent reversible cardiomyopathy, but others have displayed a dose-dependent irreversible one, which are typically caused by trastuzumab and anthracyclines, respectively. As yet, it remains unclear whether muscle strength is associated with cardiac function in patients with breast cancer and whether chemotherapy-induced muscle wasting is reversible and/or dose-dependent. In predicting and diagnosing of cardiac dysfunction, biomarkers such as Btype natriuretic peptide and cardiac troponin have shown promising results as well as echocardiography. Namely, elevated B-type natriuretic peptide and increased cardiac troponin were associated with subsequent left ventricular dysfunction and cardiovascular events, respectively, and abnormal strain imaging in echocardiography is currently the strongest predictor of cardiotoxicity. On the other hand, no biomarker has been developed for the prediction and diagnosis of muscle wasting, despite extensive research. Furthermore, conventional medical therapy for heart failure such as beta-blockers and angiotensin-converting-enzyme inhibitors (ACEi) had favourable effects on anthracycline-induced cardiomyopathy, while there might be no established treatment for muscle wasting, with the exception of exercise training. It is still under debate whether ACEi have protective effects on muscle wasting, although ACEi failed to prevent sarcopenia in older subjects. It seems important to focus on the similarities and differences between cardiac dysfunction and impaired muscle strength in patients with breast cancer.