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

    Myostatin signaling is up-regulated in female patients with advanced heart failure Junichi Ishida, Masaaki Konishi, Masakazu Saitoh, Markus Anker, Stefan D. Anker, Jochen Springer PII: DOI: Reference:

S0167-5273(17)32064-8 doi: 10.1016/j.ijcard.2017.03.153 IJCA 24835

To appear in:

International Journal of Cardiology

Received date: Revised date: Accepted date:

30 August 2016 31 March 2017 31 March 2017

Please cite this article as: Ishida Junichi, Konishi Masaaki, Saitoh Masakazu, Anker Markus, Anker Stefan D., Springer Jochen, Myostatin signaling is up-regulated in female patients with advanced heart failure, International Journal of Cardiology (2017), doi: 10.1016/j.ijcard.2017.03.153

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Original Paper

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heart failure

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Myostatin signaling is up-regulated in female patients with advanced

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Junichi ISHIDA, MD, PhD,1 Masaaki Konishi, MD, PhD,1 Masakazu Saitoh, PhD,1

Innovative Clinical Trials, Department of Caridiology and Pneumology, University

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Markus Anker, MD,2 Stefan D. Anker, MD PhD1 and Jochen SPRINGER, PhD1

Medical Centre Göttingen, Göttingen, Germany Department of Cardiology, Charité - Campus Benjamin Franklin (CBF), Berlin, Germany

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Running Title: MYOSTATIN UPREGULATION IN FEMALE HF.

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Corresponding author: Jochen Springer, PhD

Innovative Clinical Trials Department of Caridiology and Pneumology University Medical Centre Göttingen Robert-Koch-Str. 40, 37075 Göttingen, Germany Tel: +49 (0) 551 39-6380 Fax: +49 (0) 551 39-6389 E-mail: [email protected]

Key words: chronic heart failure; myocardium; myostatin signaling; gender difference

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This paper contains 2 figures and 1 table.

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ABSTRACT

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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 Although there are disparities in pathophysiology and

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loss in animal models with HF.

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epidemiology between male and female patients with HF, it remains unclear whether

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there is gender difference in myostatin expression and whether it is associated with weight loss in HF patients.

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Methods: Heart tissue samples were collected from patients with advanced heart failure Expression

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(n=31, female n=5) as well as healthy control donors (n=14, female n=6).

levels of myostatin and its related proteins in the heart were evaluated by western

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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.

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Conclusion:

In this study, myostatin and pSmad2 were significantly up-regulated in

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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

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causally contribute to pathogenesis of HF and cardiac cachexia.

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Introduction

advance.

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Heart failure (HF) is still a major clinical problem, despite the recent therapeutic Epidemiological studies have shown that men have a higher incidence of

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heart failure but that the overall prevalence rate is similar in men and women, because

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female patients with HF, even if it is severe, appear to have better survival than male

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patients [1,2]. However, clinical evidences focusing on sex differences in HF are lacking.

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Myostatin, a member of transforming growth factor b (TGF- b), is mainly expressed in

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skeletal muscle and act as a negative regulator of skeletal muscle mass [3]. .

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Myostatin is also produced in the heart and is up-regulated under the pathological conditions such as myocardial infarction, cardiac hypertrophy and HF [4-6].

On the

other hand, exercise training significantly decreased myostatin expression in both skeletal muscles and the heart [7] and exercise intervention was more effective in female patients with coronary artery disease, compared to male counterparts [8]. Furthermore, Heinke et al demonstrated that genetic deletion of myostatin from the heart protected from skeletal muscle atrophy in HF, that heart-specific overexpression of myostatin resulted in skeletal muscle loss, and that skeletal muscle atrophy in HF was suppressed by blocking myostatin using neutralized antibody [9], suggesting

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detrimental effects of cardiac myostatin on skeletal muscles.

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The aim of this study is to investigate whether there is a gender difference in expression

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of myostatin and other proteins related to myostatin signaling in the failing heart and whether myostatin expression is associated with skeletal muscle wasting, roughly assessed by body mass index.

Methods

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Cardiac tissues

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Samples of human LV tissue were obtained immediately after removal of the heart of

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patients with advanced heart failure (n=31) and stored at -80oC until further use. Tissues used in this study were taken from a slice of the papillary muscle to reduce the Tissue samples from healthy donors, who were

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variability among samples.

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pronounced brain dead, were taken from donor hearts (n=14) as soon as the heart had

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been found unsuitable for transplantation by expert cardiac surgeons and stored the same way. All surgeries were performed in 2000 or 2001.

All procedures have been

approved by the local ethics committees. Western Blotting

Approximately 50 mg of tissues were pulverized, homogenized in 500 ml lysis buffer (20 mM Tris pH 7.5, 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton-X100, 2.5 mM Na4P2O7, 1% phosphatase inhibitor (P2850, Sigma), 20 mM NaF, 1 mM DTT, 1 mM Na3VO4, 1 mM b-glycerophosphate) and centrifuged at 12000 rpm for 5 minutes at 4oC. Then, 30 mg of each sample was electrophoresed on a 12% SDS-polyacrylamide

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gel (12% polyacrylamide, 0.38 M Tris pH 8.8, 0.1% SDS, 0.1% APS, 0.04% TEMED).

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Proteins were transferred PVDF membrane using a standard semi-dry electrophoretic transfer apparatus (Trans-Blot, Bio-Rad). The membrane was blocked with 5% BSA Immunoblotting was performed to

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in Tris-buffered saline containing 0.05% Tween 20.

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detect myostatin (AF788, R&D Systems), Akt (9272, Cell Signaling), pAkt (Ser473;

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4051, Cell Signaling), pAkt (Thr308; 9275, Cell Signaling), pSmad-2 (3101, Cell Signaling), 4E-BP1 (53H11; 9644, Cell Signaling), p4E-BP1 (Thr 37/47; 9459, Cell

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Signaling), p4E-BP1 (Ser65; 9451, Cell Signaling), GSK-3a (9338, Cell Signaling),

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GSK-3b (27C10; 9315, Cell Signaling), pGSK-3a, pGSK-3b (Ser9; 37F11; 9320, Cell

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Signaling) and GAPDH (G9545; Sigma). Appropriate secondary antibodies were used. Protein bands were analyzed with ImageJ (Image Processing and Analysis in Java) and bands were normalized to the GAPDH band as a loading control. Statistics

Data were analyzed using GraphPad PRISM 5.0 (GraphPad Software, Inc, La Jolla, CA, USA). Results are shown as mean ± standard deviation(SD). Data were tested for normal distribution using the D'Agostino & Pearson omnibus normality test.

Data

with normal distribution were analyzed with Students t-test, while data without normal distribution were analyzed Mann Whitney U-test between two groups.

One-way

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analysis of variance (ANOVA) with post-hoc test by Bonferroni was performed to

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Correlation analysis was

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examine statistical differences among three or four groups.

performed using Pearson's correlation coefficient or Spearman’s rank correlation

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coefficient, for normal or skewed distributed data, respectively.

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was considered statistically significant.

A p value of <0.05

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Results

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The mean age of donors and

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Pre-explant data of study subjects are shown in Table 1.

patients with heart failure were 47.2±18.3 and 46.1±12.0 years, respectively.

In female HF patients, body mass index (BMI)

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donors and 5 patients were female.

Six

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was significantly lower than in male HF patients (20.0±4.2 in female vs 25.2±3.8 in

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male, p=0.04). There was no significant difference in other clinical variables including heart rate and echocardiographic parameters between male and female patients with HF.

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Protein analysis showed that mature form myostatin (25 kDa) and pSmad2 were

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significantly up-regulated in the myocardium of female HF patients by 1.9 fold (p<0.05)

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and 2.5 fold (p<0.01) compared to female donors, and by 1.6 fold (p<0.05) and 1.6 fold (p<0.01) compared to male HF patients, respectively (Figure 1). There was no significant difference in cardiac expression of mature myostatin between male patients and donors, while significant up-regulation of pSmad2 was observed by 2.8 times (p<0.01) in male HF patients compared with male donors (Figure 1).

There was a

positive correlation in patients with HF between Myostatin and pSmad2 expression (r=0.46, p=0.01), while not in donors (r=0.09, p=0.75) (Figure 1).

In order to evaluate

whether lower body mass index (BMI, weight [kg]/height [m2]) in female patients was associated with expression of myostatin and pSmad, male patients were divided into

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two groups with the median value of BMI and compared each other and with female

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Indeed, there was no significant difference in expression of myostatin and

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patients.

pSmad among male patients with low BMI (22.2 kg/m2), those with high BMI (28.7

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kg/m2) and female patients (Figure 1).

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In the failing heart of female HF patients, phosphorylation of Akt was decreased by 0.8

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fold compared to female donors, while it was increased by 1.4 fold in male HF patients compared with male donors, both of which did not reach statistical significance (Figure

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2). Additionally, there was no significant difference in expression of Akt pathway

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such as phosphorylation of 4E-BP and phosphorylation of GSK-3b between HF patients

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and healthy subjects in each gender (Figure 2).

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Discussion

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In the present study, female patients with advanced HF displayed significant up-regulation of mature myostatin and pSmad2 in the myocardium, compared with In addition, BMI was significantly

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female healthy subjects and male counterparts.

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lower in female patients with advanced HF than male ones.

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Several studies have shown that myostatin expression was increased in the heart of animal HF models and patients with HF [6,10], while it remains unclear whether there The present study

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is a gender difference in myostatin expression in this condition.

In

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showed that myostatin signaling is particularly increased in female failing heart.

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line with previous research [11], female HF patients undergoing heart transplant had lower BMI than male counterparts.

Low BMI as well as weight loss is a prognostic

factor for mortality in both chronic HF and acute HF [12-14], while there is no significant difference in mortality between male and female HF patients undergoing heart transplantation [15]. Myostatin was up-regulated in skeletal muscles as well as in the heart of patients with HF [7].

In addition, both Muscle RING-finger protein-1 expression and proteasome

activity were increased in skeletal muscle, suggesting enhanced protein degradation [16]. Recently, increased adiponectin has been noted to show unfavorable effects on

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HF-associated metabolic failure and muscle wasting [17].

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Interestingly, heart-specific deletion of myostatin attenuated skeletal muscle atrophy in an animal model of HF, indicating that increased myostatin signaling was associated

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with muscle wasting in HF [9]. On the other hand, treadmill exercise training for 4

Exercise training is also effective in HF patients,

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and the heart of HF rats [7].

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weeks significantly reduced myostatin protein expression in both the skeletal muscle

preventing skeletal muscle atrophy [18] as well as improving HF-associated symptoms

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[19]. A recent study demonstrated that cardiac rehabilitation significantly reduced

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long-term mortality in female patients with coronary artery disease, compared to male

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counterparts [8], which indicates a gender difference in effectiveness of exercise treatment and possible molecular mechanisms including myostatin signaling. Based on these findings, pharmacologic inhibition of myostatin is thought to be promising for the treatment of skeletal muscle wasting associated with chronic diseases and/or ageing.

Indeed, myostatin antibody prevented muscle wasting as well as

improved muscle function in a mouse model of cancer cachexia [20,21]. Moreover, myostatin antibody reduced muscle wasting in ageing mice [22,23].

Inhibition of

myostatin signaling could be also effective for the treatment of skeletal muscle loss associated with HF.

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This study has some limitations, which have to be pointed out.

First, muscle volume

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as well as muscle strength was not evaluated, because there are limited tools available to diagnose of skeletal muscle loss. C-terminal agrin-fragment (CAF) has been recently

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noted as a useful biomarker to detect muscle wasting in patients with HF [24], while

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combining several biomarkers might be better to increase the sensitivity and the

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specificity for muscle wasting [25,26]. Additionally, the patients in our study had HF with several etiologies including DCM, ICM and RCM, by which expression levels of

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myostatin could be affected [6].

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In conclusions, the present study demonstrated that both myostatin and pSmad were

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significantly up-regulated in the failing heart of female patients, who had lower BMI. Enhanced myostatin signaling in female failing heart may causally contribute to pathogenesis of HF and cardiac cachexia.

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Figure legends

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Figure 1. (A-F) Western blots for myostatin (25 kDa), latent form of myostatin (50kDa), activin receptor type-2B, follistatin and phosphor-smad2 in the heart of donors and HF Data were expressed as mean ± SD. (G) Correlation between

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patients by gender.

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myostatin and pSmad2 in donors and patients. (H, I) Western blots for myostatin (25

(28.7 kg/m2) and female patients.

*P < 0.05 from values obtained in corresponding

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donors.

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kDa) and pSmad2 in male patients with low BMI (22.2 kg/m2), those with high BMI

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Figure 2. (A-K) Western blots for Akt, phosphorylated Akt, 4E-BP, phosphorylated 4E-BP, glycogen synthase kinase-3a (GSK-3a), phosphorylated GSK-3a, GSK-3b and phosphorylated GSK-3b in the heart of donors and HF patients by gender. expressed as mean ± SD.

Data were

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Fig. 1

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Fig. 2

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Table I. Patient charateristics

HF

Female

Male

N

8

6

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Age (years)

44 ± 20

52 ± 16

46 ± 10

Body weight (kg)

79.0 ± 8.1

73.0 ± 6.7

78.2 ± 12.4

54.8 ± 15.4 *

BMI (kg/m2)

25.1 ± 2.4

23.3 ± 3.1

25.2 ± 3.8

20.0 ± 4.2 *

Heart rate (bpm)

N/A

N/A

87 ± 12

77 ± 18

Hemoglobin (g/dL)

N/A

N/A

13.0 ± 0.5

13.2 ± 0.7

Creatinine (mg/dL)

N/A

N/A

1.3 ± 0.1

1.1 ± 0.1

-

25/0/1

3/1/1

N/A

16 ± 7

23 ± 8

N/A

76 ± 10

64 ± 19

N/A

69 ± 10

56 ± 19

Etiology -

Echocardiographic data N/A

LV end-diastolic diameter

N/A

LV end-systolic dimeter

N/A

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Medication

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LV Ejection fraction (%)

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DCM/ICM/RCM (N)

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Blood exams

5

45 ± 20

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Physical exams

Female

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Male

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Donor

ACE-I/ARB

-

-

18

3

Beta-blocker

-

-

14

4

Loop diuretics

-

-

11

4

MRA

-

-

15

3

Continuous variables are presented means ± SD. Shown is a summary of clinical variables from donors and HF patients by gender. HF indicates heart failure; BMI, body mass index; DCM, dilated cardiomyopathy; ICM, ischemic cardiomyopathy; RCM, restrictive cardiomyopathy; LV, left ventricle; ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; MRA, mineralocorticoid receptor antagonist. *P < 0.05 from values obtained for male HF patients.

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Highlights:

Myostatin signaling was up-regulated in the female failing heart.

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Female patients with advanced heart failure displayed lower body mass

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-

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Enhanced myostatin signaling in the female failing heart might causally

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contribute to the pathogenesis of HF and cardiac cachexia.

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-

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compared to male counterparts.