Edited by: Corin Badiu, Carol Davila University of Medicine and Pharmacy, Romania
Reviewed by: Luiz Augusto Casulari, University of Brasilia, Brazil; Monica Livia Gheorghiu, Carol Davila University of Medicine and Pharmacy, Romania
*Correspondence: Jowita Halupczok-Żyła,
This article was submitted to Pituitary Endocrinology, a section of the journal Frontiers in Endocrinology
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The muscle is an endocrine organ controlling metabolic homeostasis. Irisin and myostatin are key myokines mediating this process. Acromegaly is a chronic disease with a wide spectrum of complications, including metabolic disturbances.
To examine the influence of acromegaly on irisin and myostatin secretion and their contribution to metabolic profile and body composition.
In 43 patients with acromegaly and 60 controls, serum levels of irisin, myostatin, growth hormone (GH), insulin-like growth factor 1 (IGF-1), parameters of glucose, and lipid metabolism were determined. Body composition was assessed with dual-energy x-ray absorptiometry.
The irisin concentration was significantly lower in patients with acromegaly compared to controls (3.91
Decreased irisin concentrations in acromegaly may suggest impaired hormonal muscle function contributing to metabolic complications in this disorder. However, learning more about the association between myostatin and GH in acromegaly requires further studies. Nevertheless, it appears that myostatin is not critical for muscle mass regulation in acromegaly.
Currently, the skeletal muscle role is considered to extend far beyond its mechanical function. Studies of the last two decades identified the muscle as the largest endocrine organ. Its secretome consists of numerous peptides regulating multiple physiological processes in an auto-, para-, and endocrine manner, especially muscle growth and energy metabolism, but also immune, endothelial, and central nervous system function (
In 2012, Bostrom et al. discovered a new myokine—irisin, whose activity can counteract metabolic disorders in a remarkable way. Under the influence of irisin, white adipose tissue (WAT) acquires brown adipose tissue (BAT)-like properties through the formation of uncoupling protein 1 expressing beige adipocytes, which disperse energy in the process of non-shivering thermogenesis. In this regard, beige adipocytes utilize glucose and free fatty acids in a non-insulin-dependent way (
Myostatin is a member of the transforming growth factor β (TGF-β) superfamily protein abundantly expressed and secreted from muscle. Furthermore, myostatin is a potent negative regulator of muscle growth and development. It acts by inhibiting myogenic stem cells and myocytes, preventing hyperplasia and hypertrophy (
Acromegaly is a chronic systemic disease, most often caused by a benign somatotroph pituitary adenoma and may be considered a natural model of chronic GH excess. Metabolic complications are common in this disease and contribute to a 1.5–2.5 times higher standardized mortality ratio with cardiovascular disease as a major cause of death (
In this single-center cross-sectional study, 43 patients with acromegaly constituting the study group and 60 controls were enrolled. The study was approved by the bioethics committee of the Wrocław Medical University.
Diagnosis of acromegaly was compliant with international guidelines (
Clinical characteristics of the study group and controls.
Acromegaly | Controls |
|
|
---|---|---|---|
Age (years) | 67.72 ± 11.44 | 58.25 ± 12.56 | 0.531 |
Sex (men/women) | 15/28 | 21/39 | 0.840 |
IR (+/-) | 10/14 | 16/27 | 0.720 |
Prediabetes (+/-) | 7/20 | 11/40 | 0.664 |
Diabetes (+/-) | 11/32 | 10/50 | 0.268 |
Hypertension (+/-) | 28/15 | 29/28 | 0.154 |
Atherogenic dyslipidemia (+/-) | 6/37 | 6/51 | 0.602 |
Hypercholesterolemia (+/-) | 22/21 | 22/35 | 0.210 |
Cardiovascular disease (+/-) | 3/38 | 8/47 | 0.271 |
The control group consisted of patients without endocrinopathies, with the exception of diabetes and any known inflammatory disease. Controls were matched to the study group in terms of age, sex, and the occurrence of diabetes and lipid abnormalities.
For analytical purposes, the study group was further subdivided according to:
Insulin resistance (IR)—patients were assigned to the IR (+) group if diabetes was excluded and their HOMA-IR exceeded 2.1. The cutoff was chosen based on the upper quartile determined for the Polish population (
Diabetes and prediabetes (defined as impaired fasting glucose [IFG] or impaired glucose tolerance [IGT])—patients were assigned to the diabetes (+) or prediabetes (+) group according to known pre-existing diabetes or based on fasting glucose level and 75 g oral glucose tolerance test using criteria proposed by the American Diabetes Association (
Atherogenic dyslipidemia—patients were assigned to atherogenic dyslipidemia group (+) if the following criteria was met: TG >150 mg/dl and HDL-C <40 mg/dl for men and <45 mg/dl for women (
Hypercholesterolemia—patients were assigned to the hypercholesterolemia (+) group if their total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) exceeded the upper limit of the norm for the assay or were treated for hypercholesterolemia
All fasting blood samples were collected, after at least 1 h of rest. Serum aliquots were stored at −70°C. Irisin was measured by ELISA assay (Biovendor—Laboratorni medicina a.s., Czech Republic, range 0.001–5 µg/ml, sensitivity 1 ng/ml). Myostatin was measured by ELISA assay (Bioassay Technology Laboratory, Shanghai, China, range 0.5–2000 ng/L, sensitivity 0.25 ng/L). All reactions were run in duplicate.
Glucose and lipids were measured by immunochemiluminometric methods (ARCHITECT, Abbott Diagnostics). LDL-C levels were measured using the Friedewald formula (
Insulin resistance and β-cell function indices were calculated only for subjects without diabetes. Homeostasis model assessment for insulin resistance for β-cell function (HOMA-β) was calculated using the following formula: 20 × fasting insulin (μIU/ml)/fasting glucose(mmol/ml) − 3.5. Homeostasis model assessment for insulin resistance (HOMA-IR) was calculated using the following formula: fasting insulin [μIU/ml] × fasting glucose [mg/dl]/18/22.5.
For each patient, the following five atherogenic factors were calculated:
Atherogenic Index of Plasma (AIP) (
Castelli I (
Castelli II (
Atherogenic coefficient (AC) (
TG/high-density lipoprotein (HDL) ratio (
Body composition measures were assessed by dual-energy x-ray absorptiometry (DXA) using a Hologic Discovery QDR Series densitometer (Hologic Incorp. USA, APEX 4.5.2.1 software version, Windows 7 Professional system). The following body composition measures were assessed:
Total body fat percentage (% fat);
Fat mass (FM);
Fat mass index (FMI);
Fat free mass index (FFMI);
Lean mass (LM);
Lean mass index (LMI);
Appendicular lean mass index (ALMI);
Appendicular lean mass/BMI (ALM/BMI); and
Trunk body fat percentage/legs body fat percentage—reflecting the visceral to subcutaneous fat ratio (% fat trunk/% fat legs).
The Kolmogorov–Smirnov test was performed to assess the normality assumption. The number of cases in each category was compared using the Chi-square or Fisher exact test. The unpaired
There were no significant differences between the study group and controls in age, sex, insulin resistance, prediabetes, diabetes, hypertension, lipid disturbances, and known cardiovascular disease (
Patients with acromegaly demonstrated significantly lower serum irisin concentrations than controls (3.91
Laboratory parameters in patients with acromegaly and controls.
Acromegaly | Controls |
|
|
---|---|---|---|
Irisin (μg/ml) | 3.91 (2.08–19.60) | 5.09 (2.50–12.70) | 0.006* |
Myostatin (ng/L) | 91.75 (56.90–1766.40) | 348.53 (59.62–1619.32) | 0.220 |
GH (ng/ml) | 1.32 (0.05–29.50) | 0.25 (0.05–5.54) | <0.001* |
IGF-1 (ng/ml) | 182.17 ± 115.62 | 112.5 ± 42.27 | <0.001* |
Glucose (mg/dl) | 97.63 ± 13.94 | 92.62 ± 14.42 | 0.093 |
HbA1c (%) | 6.10 (5.10–9.50) | 5.5 (4.70–12.40) | 0.001* |
Insulin (μIU/ml) | 7.81 (2.00–38.30) | 7.99 (2.00–30.50) | 0.477 |
HOMA-IR | 1.68 (0.37–4.74) | 1.67 (0.42–8.59) | 0.561 |
HOMA-β | 94.75 ± 54.15 | 139.18 ± 92.60 | 0.035* |
Total cholesterol (mg/dl) | 188.17 ± 47.13 | 201.04 ± 40.21 | 0.141 |
LDL-C (mg/dl) | 114.95 ± 39.27 | 123.93 ± 35.63 | 0.246 |
HDL-C (mg/dl) | 49.00 (31.00–84.00) | 54.00 (28.00–158.00) | 0.293 |
TG (mg/dl) | 107.91 ± 47.40 | 118.73 ± 43.79 | 0.245 |
AIP | 0.29 ± 0.27 | 0.33 ± 0.25 | 0.494 |
Castelli I | 3.77 ± 0.99 | 3.89 ± 1.06 | 0.550 |
Castelli II | 2.28 ± 0.85 | 2.4 ± 0.90 | 0.504 |
AC | 2.77 ± 0.99 | 2.89 ± 1.06 | 0.550 |
TG/HDL | 2.5 ± 1.45 | 2.43 ± 1.40 | 0.776 |
BMI (kg/m2) | 29.75 ± 5.36 | 27.57 ± 5.31 | 0.046* |
FM (kg) | 29.31 ± 8.02 | 27.72 ± 9.95 | 0.401 |
LM (kg) | 51.43 ± 11.20 | 46.28 ± 10.19 | 0.022* |
%fat (%) | 35.26 ± 7.65 | 36.00 ± 7.68 | 0.642 |
FMI (kg/m2) | 10.46 ± 3.20 | 10.03 ± 3.61 | 0.545 |
FFMI (kg/m2) | 18.78 ± 2.55 | 17.24 ± 2.52 | 0.004* |
LMI (kg/m2) | 17.92 ± 2.49 | 16.45 ± 2.44 | 0.005* |
ALMI (kg/m2) | 8.00 ± 1.31 | 7.66 ± 1.40 | 0.109 |
ALM/BMI | 0.72 ± 0.19 | 0.74 ± 0.18 | 0.682 |
Results are presented as mean ± SD or median (minimum–maximum). LDL-C, LDL cholesterol; HDL-C, HDL cholesterol; TG, triglyceride; AIP, atherogenic index of plasma; AC, atherogenic coefficient; FM, fat mass; LM, lean mass; %fat, whole-body fat percentage; FMI, fat mass index; FFMI, fat free mass index; LMI, lean mass index; ALMI, appendicular lean mass index; ALM/BMI, appendicular lean mass to BMI ratio.
*Statistically significant (p<0.05).
Serum GH and IGF-1 levels were significantly higher in patients with acromegaly compared to controls (0.25 ng/ml
Comparison of the patients with active acromegaly, controlled disease, and controls did not reveal significant differences in irisin and myostatin serum concentrations (
Circulating myokine concentrations in patients with active acromegaly, controlled acromegaly, and controls.
Active acromegaly | Controlled acromegaly | Controls |
|
|
---|---|---|---|---|
Irisin (μg/ml) | 4.59 ± 2.32 | 4.75 ± 3.66 | 5.28 ± 1.97 | 0.502 |
Myostatin (ng/L) | 105.20 (60.06–1,467.04) | 91.56 (56.92–1,766.41) | 348.53 (59.62–1,619.32) | 0.394 |
In the subgroup analyses of patients with acromegaly, those with IR had significantly lower serum irisin (2.80
Circulating myokine concentrations in acromegaly patients with and without selected complications.
Complication present (+) | Complication absent (-) |
|
|||||
---|---|---|---|---|---|---|---|
Irisin (μg/ml) | Myostatin (ng/L) | Irisin (μg/ml) | Myostatin (ng/L) | Irisin | Myostatin | ||
IR | 2.80 (2.15–19.60) | 81.46 (56.92–269.21) | 4.18 (2.40–10.95) | 429.58 (74.02–1,467.04) | 0.047 | 0.018* | |
Prediabetes | 2.82 (2.44–4.08) | 91.75 (56.92–1,315.92) | 4.25 (2.08–19.60) | 227.83 (60.06–1,766.41) | 0.128 | 0.847 | |
Diabetes | 4.88 ± 3.51 | 137.14 ± 83.51 | 4.62 ± 1.76 | 413.92 ± 516.62 | 0.816 | 0.09 | |
Hypercholesterolemia | 3.42 (2.13–10.95) | 134.65 (56.92–1,766.41) | 4.43 (2.08–19.60) | 88.28 (61.36–1,421.98) | 0.444 | 0.325 | |
Atherogenic dyslipidemia | 3.18 (2.44–5.70) | 105.20 (69.26–865.09) | 4.03 (2.08–19.60) | 91.56 (56.92–1,766.41) | 0.483 | 0.986 |
*Statistically significant (p<0.05).
The circulating levels of irisin and myostatin did not significantly differ among subgroups of patients with acromegaly divided according to prediabetes, diabetes, hypercholesterolemia, and atherogenic dyslipidemia (
In patients with acromegaly, irisin was negatively correlated with fasting insulin (
Correlations of the circulating myokine concentrations with metabolic parameters in patients with acromegaly.
Acromegaly | Controls | |||||||
---|---|---|---|---|---|---|---|---|
Irisin | Myostatin | Irisin | Myostatin | |||||
|
|
|
|
|
|
|
|
|
Age (years) | 0.082 | 0.603 | −0.293 | 0.056 | −0.429* | 0.016* | 0.162 | 0.250 |
GH (ng/ml) | 0.083 | 0.599 | −0.306* | 0.049* | −0.044 | 0.842 | 0.273 | 0.786 |
IGF-1 (ng/ml) | −0.206 | 0.185 | −0.209 | 0.177 | 0.217 | 0.320 | 0.032 | 0.974 |
Glucose (mg/dl) | −0.162 | 0.313 | −0.297 | 0.059 | 0.165 | 0.171 | 0.045 | 0.752 |
HbA1c (%) | 0.135 | 0.432 | −0.202 | 0.236 | 0.284 | 0.080 | 0.076 | 0.650 |
Insulin (μIU/ml) | −0.367* | 0.042* | −0.429* | 0.016* | −0.191 | 0.382 | −0.150 | 0.324 |
HOMA-IR | −0.510* | 0.011* | −0.411* | 0.046* | −0.194 | 0.374 | −0.146 | 0.374 |
HOMA-β | −0.049 | 0.821 | −0.371 | 0.074 | −0.121 | 0.584 | −0.118 | 0.752 |
Total cholesterol (mg/dl) | −0.187 | 0.229 | 0.203 | 0.192 | 0.393 | 0.064 | 0.033 | 0.818 |
LDL-C (mg/dl) | −0.283 | 0.076 | 0.243 | 0.130 | 0.291 | 0.177 | 0.042 | 0.769 |
HDL-C (mg/dl) | 0.257 | 0.097 | 0.073 | 0.638 | 0.174 | 0.428 | 0.190 | 0.181 |
TG (mg/dl) | −0.102 | 0.515 | −0.164 | 0.292 | 0.108 | 0.623 | −0.152 | 0.292 |
AIP | −0.199 | 0.201 | −0.134 | 0.392 | −0.053 | 0.810 | −0.160 | 0.273 |
Castelli I | −0.416* | 0.005* | 0.168 | 0.281 | 0.039 | 0.860 | −0.163 | 0.257 |
Castelli II | −0.400* | 0.010* | 0.193 | 0.233 | 0.015 | 0.946 | −0.105 | 0.462 |
AC | −0.417* | 0.005* | 0.168 | 0.281 | 0.039 | 0.860 | −0.163 | 0.257 |
TG/HDL | −0.199 | 0.201 | −0.134 | 0.392 | −0.050 | 0.822 | −0.184 | 0.201 |
BMI (kg/m2) | −0.060 | 0.705 | −0.246 | 0.112 | 0.067 | 0.761 | −0.277* | 0.047* |
FM (kg) | 0.074 | 0.639 | −0.176 | 0.264 | 0.140 | 0.525 | −0.153 | 0.292 |
LM (kg) | −0.184 | 0.243 | −0.106 | 0.503 | −0.080 | 0.716 | −0.325* | 0.024* |
%fat (%) | 0.140 | 0.376 | −0.025 | 0.875 | 0.133 | 0.546 | 0.104 | 0.477 |
FMI (kg/m2) | 0.073 | 0.645 | −0.143 | 0.366 | 0.150 | 0.493 | −0.089 | 0.545 |
FFMI (kg/m2) | −0.118 | 0.458 | −0.266 | 0.089 | −0.065 | 0.767 | −0.368* | 0.01* |
LMI (kg/m2) | −0.125 | 0.430 | −0.267 | 0.087 | −0.072 | 0.743 | −0.367* | 0.001* |
ALMI (kg/m2) | −0.163 | 0.301 | −0.191 | 0.226 | −0.105 | 0.633 | −0.390* | 0.006* |
ALM/BMI | −0.122 | 0.440 | 0.070 | 0.656 | −0.090 | 0.683 | −0.221 | 0.131 |
LDL-C, LDL cholesterol; HDL-C, HDL cholesterol; TG, triglyceride; AIP, atherogenic index of plasma; AC, atherogenic coefficient; FM, fat mass; LM, lean mass; %fat, whole-body fat percentage; FMI, fat mass index; FFMI, fat free mass index; LMI, lean mass index; ALMI, appendicular lean mass index; ALM/BMI, appendicular lean mass to BMI ratio.
*Statistically significant (p<0.05).
In patients with acromegaly, myostatin was negatively correlated with GH, fasting insulin, and HOMA-IR. In controls, myostatin was negatively correlated with BMI (
Irisin and myostatin are crucial myokines participating in the regulation of metabolic homeostasis controlled by the muscle. Acromegaly is a systemic disorder with many complications, including metabolic disturbances. Therefore, we investigated the myokine secretion profile in patients with different activity of acromegaly.
For the first time, we showed that acromegaly is associated with decreased circulating irisin levels, which points toward the negative impact of chronic GH excess on irisin secretion. Nonetheless, this association does not appear to be connected with GH levels directly, as there was no statistically significant difference between active and controlled acromegaly groups, and irisin did not correlate with GH and IGF-1 levels. A decrease in irisin secretion seems to be a sustained effect of chronic supraphysiological GH levels, persistent even after achieving the normal hormonal status. This would not be surprising given the fact that the control of acromegaly in many cases causes an improvement rather than a full recovery from the disease complications (
The factors associated with irisin levels in acromegaly patients were insulin resistance indices (HOMA-IR, fasting insulin) and atherogenic factors (Castelli I Castelli II, AC). Moreover, in the subgroup analysis, patients with acromegaly and IR had lower serum irisin concentration than those without IR. These findings likely reflect the beneficial effect of irisin on carbohydrate metabolism in this group of patients. The results in the study group differ from the controls, for whom irisin correlated only with age. Irisin is an insulin-sensitizing hormone, which has a positive effect on lipid profile through its pleiotropic action. Despite this, the majority of studies (
On the basis of the results of our study, we hypothesize that there is a long-lasting impairment in hormonal muscle function in conditions of long-term GH excess that contributes to the development of metabolic complications. Decreased irisin concentrations are associated with muscle pathology. Whereas acute muscle injury may cause increased irisin levels (
Current knowledge about myokine profile in acromegaly is scarce, and circulating irisin levels in this disease were evaluated only in one study by Calan et al. (
To the best of our knowledge, this is the first study assessing myostatin levels in acromegaly. We found no significant differences in circulating myostatin levels between patients with acromegaly, neither active nor controlled, and controls. Nevertheless, further data analysis demonstrated that serum myostatin in the study group was negatively correlated with GH levels. This observation points towards negative regulation of myostatin levels by GH in acromegaly. The effect of GH on myostatin secretion is not clearly established in general. There are several
Serum myostatin concentration in the study group was negatively correlated with HOMA-IR and fasting insulin. Additionally, myostatin was significantly lower in the subgroup of acromegalics with IR compared to those without IR. Myostatin is more than a muscle mass regulator and has a well-established, powerful effect on glucose metabolism, mostly through insulin antagonism (
This study has several limitations. First, a small sample size, resulting from the rarity of the disease, determines low statistical power. Second, the reliability of the measurement of irisin with ELISA is debated as antibodies used in this method may lack specificity (
Acromegaly is associated with impaired hormonal muscle function characterized by lower irisin secretion independent of the control of the disease. The decrease in irisin secretion may be involved in the development of metabolic complications in this disease. We are first to document the negative association of circulating myostatin levels with GH in acromegaly, which points toward GH as a negative regulator of myostatin secretion; however, this association does not appear to impact muscle mass in this disease significantly.
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
The studies involving human participants were reviewed and approved by the Bioethics Committee at Wroclaw Medical University. The patients/participants provided their written informed consent to participate in this study.
ŁM, MB, and JD designed the project. The first draft of the manuscript was written by ŁM. JH-Ż, MB, and JD wrote, reviewed, and edited the manuscript. Data collection was performed by JH-Ż. KK and AZ performed laboratory measurements and wrote a section of the manuscript. DJ was responsible for body composition measures. JG performed the statistical analysis. All authors contributed to the final version of the manuscript and approved it for publication.
This study was supported by grant number SUB.C120.20.016 (Ministry of Science and Higher Education).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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