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Data regarding the relation between serum myostatin level, type I interferon-inducible gene expression and insulin resistance in dermatomyositis patients are limited. This study aimed to assess serum myostatin level, homeostatic model assessment of insulin resistance (HOMA-IR) and type I interferon-inducible gene expression in dermatomyositis patients. We evaluated the role of serum myostatin level, and type I interferon-inducible gene expression in the pathogenesis of dermatomyositis as well as the relation of serum myostatin level and type I interferon-inducible gene expression to the occurrence of insulin resistance. We evaluated serum levels of myostatin and HOMA-IR utilizing ELISA as well as IFIT1 and Mx1(MxA) gene expression with RT-PCR in 25 dermatomyositis patients (group A) and 25 obviously sound subjects as controls (group B).
Results
Among group A, body mass index, serum levels of myostatin, fasting insulin, HOMA-IR, IFN-inducible genes Mx1 and IFIT1 were more significantly increased as well as; serum level of myostatin was positively correlated with age, gender, fasting insulin level, body mass index, and HOMA-IR.
Conclusions
Serum level of myostatin, Mx1 and IFIT1 gene expression act as hazard factors of insulin resistance in group A.
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HOMA-IR
Homeostatic model assessment of insulin resistance
IFN
Interferon
MxA
Myxovirus resistance A
BMI
Body mass index
IFIT1
Interferon induced protein with tetratricopeptide repeats 1
Background
Dermatomyositis is an idiopathic inflammatory myopathy that is associated with high morbidity and mortality [1]. Myostatin is communicated in skeletal muscle cells, cardiomyocytes, macrophages and vessels [2]. Stomach heftiness, androgens, and skeletal bulk are the significant parts that are associated with amalgamation and delivery of myostatin [3].
Moreover, an increase in the serum level of myostatin in obese patients was positively correlated with insulin resistance in a skeletal muscle mass-independent manner [4].
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Tissue damage in dermatomyositis derives from a self-destructive overactivation of the innate immune system as profiling of gene expression of muscle in dermatomyositis cases in comparison with those normal healthy subjects has suggested that a gene transcriptional signature is dominated by the up-regulation of interferon- (IFN)–inducible genes. In addition, plasmacytoid dendritic cells are natural IFN -producing cells that are present in dermatomyositis muscle. Also, interferon-induced protein myxovirus resistance A (MxA) is expressed in capillaries and perifascicular myofibers [5].
However, the relation between serum myostatin level, type I interferon-inducible gene expression and insulin resistance in patients with dermatomyositis has not been examined closely. We meant to assess serum myostatin level, homeostatic model assessment of insulin resistance (HOMA-IR) and type I Interferon–inducible gene expression in dermatomyositis patients. We evaluated the role of serum myostatin level, and type I interferon–inducible gene expression in the pathogenesis of dermatomyositis as well as the relation of serum myostatin level and type I interferon–inducible gene expression to the occurrence of insulin resistance.
Methods
A prospective case–control study was performed in outpatient clinics and inpatient departments of Neurology, Rheumatology and Rehabilitation of our university hospitals. Initially, 73 consecutive dermatomyositis patients were enrolled between January 2021 and January 2023 who fulfilled the 2017 European League Against Rheumatism and American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies [6]. The patients with previous history of diabetes mellitus, malignant tumor, infectious diseases, thyroid disorders, hypertension, ischemic heart disease, cardiac failure, chronic obstructive pulmonary disease, liver and kidney failure, in use of statins were excluded. Thus, only twenty-five out of the initial 73 dermatomyositis patients (group A) were included in the current study along with 25 healthy participants (group B) selected in the same period, and matched for age, gender, ethnicity, weight, height, and ethnicity.
A written informed consent was obtained from the included participants, and the ethics committee on research involving human subjects of our faculty of medicine approved this study.
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Each patient was subjected to a complete history taking with special stress on age, age at disease onset, gender, ethnicity, disease duration, and tobacco use. Complete general examination including current waist circumference, weight, height, calculation of body mass index (BMI), and measurement of blood pressure was done for all participants. Neurological clinical examination with special stress on skin manifestations was done.
After 12 h fasting period, 15 ml venous blood sample was drawn in the morning from all participants, immediately (less than 30 min) centrifuged at 3000 rpm for ten minutes at 4 °C, and processed.
Levels of serum fasting insulin and plasma glucose levels were analyzed. We calculated insulin resistance using a homeostasis model assessment of insulin resistance (HOMA-IR) that was measured according to the following formula: fasting plasma glucose (mmol/l) × fasting plasma insulin concentration (μIU/ml)/22.5 and it was defined as a HOMA-IR more than four [7].
We additionally, estimated serum level of myostatin using a commercially available ELISA kit (R and D Systems DGDF eighty, Minneapolis, USA). Serum level of myostatin was estimated fully blinded to clinical or other laboratory data of the participants. We measured its absorbance at 450 nm using a Spark plate reader (Tecan, Switzerland), with an intra-assay coefficient of variation below twelve percent, inter-assay coefficient of variation below fourteen percent, and limit of blank LoB is 0.370 ng/ml according to the manufacturer’s data. Han and colleagues reported that the serum myostatin level was 7 ± 2.5 ng/ml in healthy subjects [8]
Total extraction of RNA from 1 × 106 cells was done following the manufacturer’s instructions using the RNeasy Mini kit (Qiagen). We performed quantitative real-time reverse transcriptase–polymerase chain reaction (RT-PCR) for two IFN-inducible genes: interferon induced protein with tetratricopeptide repeats 1(IFIT1) and Mx1(MxA).
Primers used were as follows: for MxA, F.5′-CGGCTAACGGATAAGCAGAG-3′ and R. 5′-ACCTACAGCTGGCTCCTGAA-3′; for IFIT1, F. 5′-AAAAGCCCACATTTGAGGTG-3′ and R. 5′- GAAATTCCTGAAACCGACCA-3′ (reverse). Reverse transcription of the RNA by QuantiTect Reverse Transcription Kit (Qiagen) was performed. Analysis of IFIT1 and MxA genes expression was done using cDNA products. Quantitative real-time PCR analysis was carried out in which each run consisted of after an initial denaturation step at 95 °C for 5 min, conditions for cycling were 40 cycles of denaturation at 95 °C for 30 s, annealing at 57 °C for thirty seconds, and extension at 72 °C for 1 min. The expressed data were normalized by GAPDH that was used as a housekeeping gene.
Statistical analysis
All variables including demographic, clinical and laboratory indicator data were expressed as count (%) or mean ± SD. All statistical analyses were done by utilizing the statistical package for the social sciences version 24 which is released in 2016 by the International Business Machines Corporation, USA. We utilized Chi-square test, Fisher's exact test, independent samples t-test, Pearson correlation analysis, Spearman correlation analysis and multivariate regression analysis between serum levels of myostatin and other variables when needed. A value of P was set at less than 0.05 for significant results.
Results
Body mass index was more significantly increased in group A (Table 1).
Table 1
Demographic and clinical indicator data of both groups
Demographic and clinical characteristics
Group
P value
A
B
Age (years)
52.63 ± 12.68
51.28 ± 14.11
0.724
Sex
Female
80% (20/25)
84% (21/25)
0.716
Male
20% (5/25)
16% (4/25)
Weight (kg)
74.19 ± 15.37
72.28 ± 12.54
0.632
Height (m)
1.74 ± 9.11
1.71 ± 9.12
0.991
Body mass index (kg/m2)
28.15 ± 4.87
25.56 ± 3.81
0.041*
Waist circumference (cm)
97.1 ± 13.1
94.3 ± 12.4
0.441
Disease duration (years)
11.40(4.32–15.51)
–
–
Articular involvement
36% (9/25)
–
–
Dysphagia
40% (10/25)
–
–
Dysphonia
16% (4/25)
–
–
Cutaneous involvement
Heliotrope
92% (23/25)
–
–
Gottronʼs sign
88% (22/25)
–
–
“V-neck” sign
40% (10/25)
–
–
“Shawl” sign
16% (4/25)
–
–
Facial rash
24% (6/25)
–
–
Raynaud’ phenomenon
48% (12/25)
–
–
*Significant
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Serum levels of fasting insulin, HOMA-IR and myostatin were more significantly increased in group A (Table 2).
Table 2
Laboratory indicator data of the studied groups
Characteristics
Group
P value
A
B
Fasting blood glucose (mg/dl)
102.4 ± 1.82
101.9 ± 1.83
0.338
Fasting insulin (mIU/ml)
18.33 ± 1.78
16.97 ± 1.96
0.013*
HOMA-IR
3.67 ± 0.95
2.95 ± 0.99
0.012*
Serum myostatin (ng/ml)
10.36 ± 4.99
7.37 ± 4.94
0.038 *
HOMA-IR homeostasis model assessment of insulin resistance
*Significant
Blood IFN-inducible gene Mx1 and IFIT1 were up-regulated in peripheral blood mononuclear cells from group A (P values less than 0.0001) (Fig. 1).
We found that among group A, serum myostatin level positively correlated with age, gender, fasting insulin level, and HOMA-IR (Table 3).
Table 3
Correlation between myostatin and other variables
Group A
Myostatin (pg/mL)
R
P-value
Age (years)
0.824
0.04*
Gender
0.357
0.02*
Weight (Kg)
0.082
0.616
Height (m)
0.057
0.773
Body mass index (kg/m2)
0.049
0.117
Waist circumference
0.121
0.364
Fasting blood glucose (mg/dl)
0.101
0.396
Fasting insulin level (mIU/ml)
0.261
0.022*
Homeostasis model assessment of insulin resistance
0.264
0.01*
*Significant
Myostatin levels showed positive significant correlation with HOMA-IR, body mass index, and age of the studied patients (Table 4).
Table 4
Multivariate regression analysis between serum myostatin levels and other variables
Group A
Unstandardized coefficients
Standardized coefficients
t-test
P-value
B
Std. Error
Beta
Age (years)
10.316
3.064
0.245
3.367
0.01*
Gender
28.864
58.537
0.032
0.429
0.682
Body mass index (kg/m2)
14.306
7.063
0.144
2.365
0.03*
Fasting insulin level (mIU/ml)
78.314
66.547
0.060
1.176
0.252
HOMA-IR
14.974
7.123
0.181
2.069
0.04*
HOMA-IR homeostasis model assessment of insulin resistance
*Significant
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Discussion
Myostatin is a master regulator of skeletal muscle mass that plays an essential role in the communication between skeletal muscles and adipose tissue and it is involved in the uptake of glucose as well as in the response of these tissues to insulin. Also, inhibition of expression of myostatin improves insulin sensitivity [9, 10]. Insulin resistance was associated with an increased risk of atherosclerotic cardiovascular outcomes in a large population of non-Hispanic whites and Mexican American without suffering from diabetes mellitus at baseline [11].
However, the relation between serum myostatin level, type I interferon-inducible gene expression and insulin resistance in cases with dermatomyositis has not been examined closely. Therefore, we meant to assess serum myostatin level, homeostatic model assessment of insulin resistance (HOMA-IR) and type I interferon-inducible gene expression in participants with dermatomyositis. We evaluated the role of serum myostatin level, and type I interferon-inducible gene expression in the pathogenesis of dermatomyositis as well as the relation of serum myostatin level and type I interferon-inducible gene expression to the occurrence of insulin resistance.
Dermatomyositis patients showed significantly higher serum myostatin level when compared to controls. This met with findings of Kerschan-Schindl and colleagues [12]. Moreover, glucocorticoids stimulate muscles’ production of myostatin. Therefore, an increment of levels of myostatin in long-term cases with dermatomyositis can be attributed to irreversible muscle damage and/or reduced muscle mass [12].
Also, the results of another study are agreeing with our finding [13], but others are not [14, 15] as there are significant differences in the studied populations including patients’ number, clinical status and classification of idiopathic inflammatory myopathies.
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In the current study, we found that in dermatomyositis cases there was higher BMI, higher fasting serum insulin levels, and HOMA-IR. Also, serum myostatin level positively correlated with age, gender, fasting insulin level, body mass index, and HOMA-IR.
This met with the finding of another study in which they found that myostatin level was increased in obese compared to lean individuals and serum myostatin level correlated positively with insulin resistance indices and negatively with insulin sensitivity indices in humans [16].
The level of serum myostatin is linked to insulin resistance and obesity [17]. This finding could explain the insulin resistance and metabolic syndromes accompanying myositis patients with high body mass index. This met with our finding that myostatin levels positively correlated with HOMA-IR, and body mass index of the studied patients.
Myostatin or myostatin precursor accumulates and associates with aggregates containing amyloid-beta within idiopathic inflammatory myopathies muscle fibers. So, one would suspect myostatin as a good therapeutic target in those patients as inhibition of myostatin is beneficial in improving both muscle function and muscle mass [18].
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Moreover, our findings suggest that in most cases with dermatomyositis there is marked overexpression of IFN-inducible genes. Our results go hand in hand with Roberson and colleagues [7].
Conclusions
Myostatin level, IFN-inducible genes (Mx1 and IFIT1) and HOMA-IR were more significantly increased in cases presented with dermatomyositis. Level of myostatin was significantly correlated with BMI and HOMA-IR. Moreover, an inexpensive PCR-based blood test that correlates the expression of certain IFN-inducible genes with activity of dermatomyositis could supplement the clinical management of dermatomyositis and provide surrogate endpoint for treatment response. Also, interferon beta inhibition could be a novel therapy in the treatment of dermatomyositis. So, one would suspect myostatin as a good therapeutic target in those patients as inhibition of myostatin is beneficial in improving both muscle function and muscle mass.
Acknowledgements
The authors acknowledge all the subjects for their participation and cooperation in this study.
Declarations
Ethics approval and consent to participate
The study was approved from the institute research board of Faculty of Medicine, Zagazig University, Egypt (ZU-IRB# 356/12-May-2024). A written informed consent was obtained from all the participants after informing them about the study rationale and their right to withdraw from the study at any time without any consequences.
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Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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