Myostatin and the Heart
Abstract: Myostatin (growth differentiation factor 8) is a member of the transforming growth factor-β superfamily. It is secreted mostly by skeletal muscles, although small amounts of myostatin are produced by the myocardium and the adipose tissue as well. Myostatin binds to activin IIB membrane receptors to activate the downstream intracellular canonical Smad2/Smad3 pathway, and additionally acts on non-Smad (non-canonical) pathways. Studies on transgenic animals have shown that overexpression of myostatin reduces the … Show more
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Cited by 4 publications
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Systemic aging fuels heart failure: Molecular mechanisms and therapeutic avenues
Systemic aging influences various physiological processes and contributes to structural and functional decline in cardiac tissue. These alterations include an increased incidence of left ventricular hypertrophy, a decline in left ventricular diastolic function, left atrial dilation, atrial fibrillation, myocardial fibrosis and cardiac amyloidosis, elevating susceptibility to chronic heart failure (HF) in the elderly. Age‐related cardiac dysfunction stems from prolonged exposure to genomic, epigenetic, oxidative, autophagic, inflammatory and regenerative stresses, along with the accumulation of senescent cells. Concurrently, age‐related structural and functional changes in the vascular system, attributed to endothelial dysfunction, arterial stiffness, impaired angiogenesis, oxidative stress and inflammation, impose additional strain on the heart. Dysregulated mechanosignalling and impaired nitric oxide signalling play critical roles in the age‐related vascular dysfunction associated with HF. Metabolic aging drives intricate shifts in glucose and lipid metabolism, leading to insulin resistance, mitochondrial dysfunction and lipid accumulation within cardiomyocytes. These alterations contribute to cardiac hypertrophy, fibrosis and impaired contractility, ultimately propelling HF. Systemic low‐grade chronic inflammation, in conjunction with the senescence‐associated secretory phenotype, aggravates cardiac dysfunction with age by promoting immune cell infiltration into the myocardium, fostering HF. This is further exacerbated by age‐related comorbidities like coronary artery disease (CAD), atherosclerosis, hypertension, obesity, diabetes and chronic kidney disease (CKD). CAD and atherosclerosis induce myocardial ischaemia and adverse remodelling, while hypertension contributes to cardiac hypertrophy and fibrosis. Obesity‐associated insulin resistance, inflammation and dyslipidaemia create a profibrotic cardiac environment, whereas diabetes‐related metabolic disturbances further impair cardiac function. CKD‐related fluid overload, electrolyte imbalances and uraemic toxins exacerbate HF through systemic inflammation and neurohormonal renin‐angiotensin‐aldosterone system (RAAS) activation. Recognizing aging as a modifiable process has opened avenues to target systemic aging in HF through both lifestyle interventions and therapeutics. Exercise, known for its antioxidant effects, can partly reverse pathological cardiac remodelling in the elderly by countering processes linked to age‐related chronic HF, such as mitochondrial dysfunction, inflammation, senescence and declining cardiomyocyte regeneration. Dietary interventions such as plant‐based and ketogenic diets, caloric restriction and macronutrient supplementation are instrumental in maintaining energy balance, reducing adiposity and addressing micronutrient and macronutrient imbalances associated with age‐related HF. Therapeutic advancements targeting systemic aging in HF are underway. Key approaches include senomorphics and senolytics to limit senescence, antioxidants targeting mitochondrial stress, anti‐inflammatory drugs like interleukin (IL)‐1β inhibitors, metabolic rejuvenators such as nicotinamide riboside, resveratrol and sirtuin (SIRT) activators and autophagy enhancers like metformin and sodium‐glucose cotransporter 2 (SGLT2) inhibitors, all of which offer potential for preserving cardiac function and alleviating the age‐related HF burden.
Systemic aging fuels heart failure: Molecular mechanisms and therapeutic avenues
Systemic aging influences various physiological processes and contributes to structural and functional decline in cardiac tissue. These alterations include an increased incidence of left ventricular hypertrophy, a decline in left ventricular diastolic function, left atrial dilation, atrial fibrillation, myocardial fibrosis and cardiac amyloidosis, elevating susceptibility to chronic heart failure (HF) in the elderly. Age‐related cardiac dysfunction stems from prolonged exposure to genomic, epigenetic, oxidative, autophagic, inflammatory and regenerative stresses, along with the accumulation of senescent cells. Concurrently, age‐related structural and functional changes in the vascular system, attributed to endothelial dysfunction, arterial stiffness, impaired angiogenesis, oxidative stress and inflammation, impose additional strain on the heart. Dysregulated mechanosignalling and impaired nitric oxide signalling play critical roles in the age‐related vascular dysfunction associated with HF. Metabolic aging drives intricate shifts in glucose and lipid metabolism, leading to insulin resistance, mitochondrial dysfunction and lipid accumulation within cardiomyocytes. These alterations contribute to cardiac hypertrophy, fibrosis and impaired contractility, ultimately propelling HF. Systemic low‐grade chronic inflammation, in conjunction with the senescence‐associated secretory phenotype, aggravates cardiac dysfunction with age by promoting immune cell infiltration into the myocardium, fostering HF. This is further exacerbated by age‐related comorbidities like coronary artery disease (CAD), atherosclerosis, hypertension, obesity, diabetes and chronic kidney disease (CKD). CAD and atherosclerosis induce myocardial ischaemia and adverse remodelling, while hypertension contributes to cardiac hypertrophy and fibrosis. Obesity‐associated insulin resistance, inflammation and dyslipidaemia create a profibrotic cardiac environment, whereas diabetes‐related metabolic disturbances further impair cardiac function. CKD‐related fluid overload, electrolyte imbalances and uraemic toxins exacerbate HF through systemic inflammation and neurohormonal renin‐angiotensin‐aldosterone system (RAAS) activation. Recognizing aging as a modifiable process has opened avenues to target systemic aging in HF through both lifestyle interventions and therapeutics. Exercise, known for its antioxidant effects, can partly reverse pathological cardiac remodelling in the elderly by countering processes linked to age‐related chronic HF, such as mitochondrial dysfunction, inflammation, senescence and declining cardiomyocyte regeneration. Dietary interventions such as plant‐based and ketogenic diets, caloric restriction and macronutrient supplementation are instrumental in maintaining energy balance, reducing adiposity and addressing micronutrient and macronutrient imbalances associated with age‐related HF. Therapeutic advancements targeting systemic aging in HF are underway. Key approaches include senomorphics and senolytics to limit senescence, antioxidants targeting mitochondrial stress, anti‐inflammatory drugs like interleukin (IL)‐1β inhibitors, metabolic rejuvenators such as nicotinamide riboside, resveratrol and sirtuin (SIRT) activators and autophagy enhancers like metformin and sodium‐glucose cotransporter 2 (SGLT2) inhibitors, all of which offer potential for preserving cardiac function and alleviating the age‐related HF burden.
Exploring in vivo and in vitro models for heart failure with biomarker insights: a review
Background Heart failure (HF) is a condition characterized by the heart’s inability to meet the body’s demands, resulting in various complications. Two primary types of HF exist, namely HF with preserved left ventricular ejection fraction (LVEF) and HF reduced with LVEF. The progression of HF involves compensatory mechanisms such as cardiac hypertrophy, fibrosis, and alterations in gene expression. Pressure overload and volume overload are common etiologies of HF, with pressure overload often stemming from conditions like hypertension, leading to left ventricular hypertrophy and fibrosis. In contrast, volume overload can arise from chronic valvular regurgitant disease, also inducing left ventricular hypertrophy. Main body In vitro cell culture techniques serve as vital tools in studying HF pathophysiology, allowing researchers to investigate cellular responses and potential therapeutic targets. Additionally, biomarkers, measurable biological characteristics, play a crucial role in diagnosing and predicting HF. Some notable biomarkers include adrenomedullin, B-type natriuretic peptide, copeptin, galectin-3, interleukin-6, matrix metalloproteinases (MMPs), midregional pro-atrial natriuretic peptide, myostatin, procollagen type I C-terminal propeptide, procollagen type III N-terminal propeptide and tissue inhibitors of metalloproteinases (TIMPs). These biomarkers aid in HF diagnosis, assessing its severity, and monitoring treatment response, contributing to a deeper understanding of the disease and potentially leading to improved management strategies and outcomes. Conclusions This review provides comprehensive insights into various in vivo models of HF, commonly utilized cell lines in HF research, and pivotal biomarkers with diagnostic relevance for HF. By synthesizing this information, researchers gain valuable resources to further explore HF pathogenesis, identify novel therapeutic targets, and enhance diagnostic and prognostic approaches.
Prevalence of main risk factors and cytokine profile in patients with acute coronary syndrome and different serum myostatin levels
Objective. To study the prevalence of the main risk factors and the value of proinflammatory cytokines in patients with acute coronary syndrome (ACS) depending on the determined level of serum myostatin. Materials and methods. 120 patients with ST elevation ACS (STE-ACS) and non-ST-segment elevation ACS (NSTE-ACS), hospitalized in the cardiology department of the regional vascular center were examined. In 86 patients, the level of serum myostatin and proinflammatory cytokines was determined on the 5th day of the development of acute coronary syndrome. Results. Patients were divided into two subgroups depending on the level of serum myostatin which was determined: group 1 – with a lower level of myostatin, group 2 – with a higher level of myostatin. Group 1 (serum myostatin level from 0.038 to 0.084 ng/ml) consisted of 23 patients (16 males). Group 2 (serum myostatin level from 0.137 to 0.630 ng/ml) contained 21 patients (14 males). The main risk factors for cardiovascular diseases such as family history of early development of cardiovascular diseases, smoking, dyslipidemia, obesity, arterial hypertension and type 2 diabetes mellitus were assessed. The levels of pro-inflammatory cytokines were determined. Tumor necrosis factor alpha (TNF-alpha) and interleukin 18 (IL-18) levels were significantly higher in patients with higher myostatin levels. Correlation analysis revealed a relationship between serum myostatin concentration and TNF-alpha level (r = 0.34; p = 0.0016). Conclusions. No differences in the prevalence of risk factors in patients with ACS and different myostatin levels, except for smoking were revealed in the study, the frequency of smoking was higher in the group with higher myostatin levels. Greater activity of pro-inflammatory cytokines TNF-alpha and IL-18 was revealed in patients with higher levels of myostatin, as well as a significant correlation between the level of myostatin and TNF-alpha.
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