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Biomedicine & Pharmacotherapy =... May 2020Pathological cardiac hypertrophy is characterized by myocyte enlargement and cardiac dysfunction. However, the pathogenesis for this disease is still poorly understood....
Pathological cardiac hypertrophy is characterized by myocyte enlargement and cardiac dysfunction. However, the pathogenesis for this disease is still poorly understood. Stimulator of interferon genes (STING) could meditate inflammation and immune response in various kinds of diseases. In this work, we demonstrated that STING was critical for pressure overload-induced cardiac hypertrophy. Results showed that STING expression was up-regulated in human and mouse hypertrophic hearts. STING knockout attenuated cardiac hypertrophy induced by aortic banding (AB). The effects of STING deficiency on the improvement of cardiac hypertrophy and dysfunction were associated with the restrained macrophage infiltration, inflammatory response and fibrosis. Moreover, ER stress was detected in hearts of AB-operated mice, as evidenced by the increased expression of phospho-protein kinase RNA-like endoplasmic reticulum kinase (PERK), phospho-eukaryotic initiation factor 2 alpha (eIF2α) and phospho-inositol-requiring kinase (IRE)-1α. Importantly, these proteins were restrained in mice with STING knockout after AB surgery. What's more, angiotensin II (Ang II)-induced STING could be accelerated by ER stress activator, while being markedly abolished by the ER stress inhibitor. We then found that whether co-treated with or without transforming growth factor-beta 1 (TGF-β1), cardiac fibroblasts cultured in the conditional medium (CM) from Ang II-incubated cardiomyocytes with STING knockdown exhibited significantly reduced fibrosis, as displayed by the clearly down-regulated expression of α-SMA, Collagen type I (Col I) and Collagen type III (Col III). Therefore, we defined STING as an important signal contributing to cardiac hypertrophy closely associated with ER stress.
Topics: Angiotensin II; Animals; Biomarkers; Cardiomegaly; Disease Models, Animal; Disease Susceptibility; Echocardiography; Endoplasmic Reticulum Stress; Fibrosis; Gene Expression; Gene Knockdown Techniques; Immunohistochemistry; Inflammation; Male; Membrane Proteins; Mice; Myocytes, Cardiac; Rats; Signal Transduction
PubMed: 32106379
DOI: 10.1016/j.biopha.2020.110022 -
Cells Nov 2022The heart reacts to a large number of pathological stimuli through cardiac hypertrophy, which finally can lead to heart failure. However, the molecular mechanisms of... (Review)
Review
The heart reacts to a large number of pathological stimuli through cardiac hypertrophy, which finally can lead to heart failure. However, the molecular mechanisms of cardiac hypertrophy remain elusive. Actin participates in the formation of highly differentiated myofibrils under the regulation of actin-binding proteins (ABPs), which provides a structural basis for the contractile function and morphological change in cardiomyocytes. Previous studies have shown that the functional abnormality of ABPs can contribute to cardiac hypertrophy. Here, we review the function of various actin-binding proteins associated with the development of cardiac hypertrophy, which provides more references for the prevention and treatment of cardiomyopathy.
Topics: Humans; Microfilament Proteins; Cardiomegaly; Heart Failure; Myocytes, Cardiac
PubMed: 36428995
DOI: 10.3390/cells11223566 -
Aesthetic Surgery Journal Nov 2021
Topics: Botulinum Toxins; Botulinum Toxins, Type A; Humans; Hypertrophy; Injections, Intramuscular; Masseter Muscle; Neuromuscular Agents
PubMed: 34223879
DOI: 10.1093/asj/sjab273 -
Journal of the American Veterinary... Nov 2023Feline hypertrophic cardiomyopathy (HCM) remains a disease with little therapeutic advancement. Rapamycin modulates the mTOR pathway, preventing and reversing cardiac...
OBJECTIVE
Feline hypertrophic cardiomyopathy (HCM) remains a disease with little therapeutic advancement. Rapamycin modulates the mTOR pathway, preventing and reversing cardiac hypertrophy in rodent disease models. Its use in human renal allograft patients is associated with reduced cardiac wall thickness. We sought to evaluate the effects of once-weekly delayed-release (DR) rapamycin over 6 months on echocardiographic, biochemical, and biomarker responses in cats with subclinical, nonobstructive HCM.
ANIMALS
43 client-owned cats with subclinical HCM.
METHODS
Cats enrolled in this double-blinded, multicentered, randomized, and placebo-controlled clinical trial were allocated to low- or high-dose DR rapamycin or placebo. Cats underwent physical examination, quality-of-life assessment, blood pressure, hematology, biochemistry, total T4, urinalysis, N-terminal pro-B-type natriuretic peptide, and cardiac troponin I at baseline and days 60, 120, and 180. Fructosamine was analyzed at screening and day 180. Echocardiograms were performed at all time points excluding day 120. Outcome variables were compared using a repeated measures ANCOVA.
RESULTS
No demographic, echocardiographic, or clinicopathologic values were significantly different between study groups at baseline, confirming successful randomization. At day 180, the primary study outcome variable, maximum LV myocardial wall thickness at any location, was significantly lower in the low-dose DR rapamycin group compared to placebo (P = .01). Oral DR rapamycin was well tolerated with no significant differences in adverse events between groups.
CLINICAL RELEVANCE
Results demonstrate that DR rapamycin was well tolerated and may prevent or delay progressive LV hypertrophy in cats with subclinical HCM. Additional studies are warranted to confirm and further characterize these results.
Topics: Animals; Cats; Cardiomyopathy, Hypertrophic; Cat Diseases; Heart; Hypertrophy, Left Ventricular; Myocardium; Sirolimus; Delayed-Action Preparations
PubMed: 37495229
DOI: 10.2460/javma.23.04.0187 -
JCI Insight Aug 2023The growth of skeletal muscle relies on a delicate equilibrium between protein synthesis and degradation; however, how proteostasis is managed in the endoplasmic...
The growth of skeletal muscle relies on a delicate equilibrium between protein synthesis and degradation; however, how proteostasis is managed in the endoplasmic reticulum (ER) is largely unknown. Here, we report that the SEL1L-HRD1 ER-associated degradation (ERAD) complex, the primary molecular machinery that degrades misfolded proteins in the ER, is vital to maintain postnatal muscle growth and systemic energy balance. Myocyte-specific SEL1L deletion blunts the hypertrophic phase of muscle growth, resulting in a net zero gain of muscle mass during this developmental period and a 30% reduction in overall body growth. In addition, myocyte-specific SEL1L deletion triggered a systemic reprogramming of metabolism characterized by improved glucose sensitivity, enhanced beigeing of adipocytes, and resistance to diet-induced obesity. These effects were partially mediated by the upregulation of the myokine FGF21. These findings highlight the pivotal role of SEL1L-HRD1 ERAD activity in skeletal myocytes for postnatal muscle growth, and its physiological integration in maintaining whole-body energy balance.
Topics: Humans; Endoplasmic Reticulum-Associated Degradation; Ubiquitin-Protein Ligases; Proteins; Muscles; Energy Metabolism; Hypertrophy
PubMed: 37535424
DOI: 10.1172/jci.insight.170387 -
Expert Opinion on Therapeutic Targets Jan 2022Cardiac hypertrophy is associated with adverse outcomes across cardiovascular disease states. Despite strides over the last three decades in identifying molecular and... (Review)
Review
INTRODUCTION
Cardiac hypertrophy is associated with adverse outcomes across cardiovascular disease states. Despite strides over the last three decades in identifying molecular and cellular mechanisms driving hypertrophy, the link between pathophysiological stress stimuli and specific myocyte/heart growth profiles remains unclear. Moreover, the optimal strategy for preventing pathology in the setting of hypertrophy remains controversial.
AREAS COVERED
This review discusses molecular mechanisms underlying cardiac hypertrophy with a focus on factors driving the orientation of myocyte growth and the impact on heart function. We highlight recent work showing a novel role for the spectrin-based cytoskeleton, emphasizing regulation of myocyte dimensions but not hypertrophy per se. Finally, we consider opportunities for directing the orientation of myocyte growth in response to hypertrophic stimuli as an alternative therapeutic approach. Relevant publications on the topic were identified through Pubmed with open-ended search dates.
EXPERT OPINION
To define new therapeutic avenues, more precision is required when describing changes in myocyte and heart structure/function in response to hypertrophic stimuli. Recent developments in computational modeling of hypertrophic networks, in concert with more refined experimental approaches will catalyze translational discovery to advance the field and further our understanding of cardiac hypertrophy and its relationship with heart disease.
Topics: Cardiomegaly; Cardiovascular Diseases; Humans; Myocytes, Cardiac
PubMed: 35076342
DOI: 10.1080/14728222.2022.2031974 -
Advanced Science (Weinheim,... Jun 2023Inhibition of pathological cardiac hypertrophy is recognized as an important therapeutic strategy for heart failure, although effective targets are still lacking in...
Inhibition of pathological cardiac hypertrophy is recognized as an important therapeutic strategy for heart failure, although effective targets are still lacking in clinical practice. Homeodomain interacting protein kinase 1 (HIPK1) is a conserved serine/threonine kinase that can respond to different stress signals, however, whether and how HIPK1 regulates myocardial function is not reported. Here, it is observed that HIPK1 is increased during pathological cardiac hypertrophy. Both genetic ablation and gene therapy targeting HIPK1 are protective against pathological hypertrophy and heart failure in vivo. Hypertrophic stress-induced HIPK1 is present in the nucleus of cardiomyocytes, while HIPK1 inhibition prevents phenylephrine-induced cardiomyocyte hypertrophy through inhibiting cAMP-response element binding protein (CREB) phosphorylation at Ser271 and inactivating CCAAT/enhancer-binding protein β (C/EBPβ)-mediated transcription of pathological response genes. Inhibition of HIPK1 and CREB forms a synergistic pathway in preventing pathological cardiac hypertrophy. In conclusion, HIPK1 inhibition may serve as a promising novel therapeutic strategy to attenuate pathological cardiac hypertrophy and heart failure.
Topics: Humans; Cyclic AMP Response Element-Binding Protein; Cardiomegaly; Myocytes, Cardiac; Protein Serine-Threonine Kinases; Heart Failure
PubMed: 37098980
DOI: 10.1002/advs.202300585 -
Singapore Medical Journal Jul 2023Muscle fibres are multinuclear cells, and the cytoplasmic territory where a single myonucleus controls transcriptional activity is called the myonuclear domain (MND).... (Review)
Review
Muscle fibres are multinuclear cells, and the cytoplasmic territory where a single myonucleus controls transcriptional activity is called the myonuclear domain (MND). MND size shows flexibility during muscle hypertrophy. The MND ceiling hypothesis states that hypertrophy results in the expansion of MND size to an upper limit or MND ceiling, beyond which additional myonuclei via activation of satellite cells are required to support further growth. However, the debate about the MND ceiling hypothesis is far from settled, and various studies show conflicting results about the existence or otherwise of MND ceiling in hypertrophy. The aim of this review is to summarise the literature about the MND ceiling in various settings of hypertrophy and discuss the possible factors contributing to a discrepancy in the literature. We conclude by describing the physiological and clinical significance of the MND ceiling limit in the muscle adaptation process in various physiological and pathological conditions.
Topics: Humans; Muscle Fibers, Skeletal; Hypertrophy; Muscle, Skeletal
PubMed: 34544215
DOI: 10.11622/smedj.2021103 -
Journal of Cachexia, Sarcopenia and... Jun 2024Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for...
BACKGROUND
Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy.
METHODS
We used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U-C]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level.
RESULTS
The metabolomics analysis in myotubes revealed insulin-like growth factor-1 (IGF-1)-induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose-5-phosphate/ribulose-5-phosphate: +40%; P = 0.01) and serine synthesis pathway (serine: -36.8%; P = 0.009). Like the hypertrophy stimulation with IGF-1 in myotubes in vitro, the concentration of the dipeptide l-carnosine was decreased by 26.6% (P = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose-6-phosphate, fructose-6-phosphate or glucose-1-phosphate) decreased by 32.2% (P = 0.004) in the overloaded muscle in vivo while increasing in the IGF-1-stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U-C]glucose is increasingly incorporated by ~13% (P = 0.001) into the non-essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (P = 0.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (P < 0.001), highlighting the importance of the serine synthesis pathway for maintaining muscle size. Utilizing data from the UK Biobank (n = 450 243), we then discerned genetic variations linked to the serine synthesis pathway (PHGDH and PSPH) and to its downstream enzyme (SHMT1), revealing their association with appendicular lean mass in humans (P < 5.0e-8).
CONCLUSIONS
Understanding the mechanisms that regulate skeletal muscle mass will help in developing effective treatments for muscle weakness. Our results provide evidence for the metabolic rewiring of glycolytic intermediates into anabolic pathways during muscle growth, such as in serine synthesis.
Topics: Glucose; Muscle, Skeletal; Animals; Mice; Humans; Hypertrophy; Muscle Fibers, Skeletal; Insulin-Like Growth Factor I; Metabolomics
PubMed: 38742477
DOI: 10.1002/jcsm.13468 -
American Journal of Physiology.... Jul 2022Skeletal muscle is an integral tissue system that plays a crucial role in the physical function of all vertebrates and is a key target for maintaining or improving... (Review)
Review
Skeletal muscle is an integral tissue system that plays a crucial role in the physical function of all vertebrates and is a key target for maintaining or improving health and performance across the lifespan. Based largely on cellular and animal models, there is some evidence that various forms of heat stress with or without resistance exercise may enhance skeletal muscle growth or reduce its loss. It is not clear whether these stimuli are similarly effective in humans or meaningful compared with exercise alone across various heating methodologies. Furthermore, the magnitude by which heat stress may influence whole body thermoregulatory responses and the connection to skeletal muscle adaptation remains ambiguous. Finally, the underlying mechanisms, which may include interaction between relevant heat shock proteins and intracellular hypertrophy and atrophy related factors, remain unclear. In this narrative review, we examine the relevant literature regarding heat stress alone or in combination with resistance exercise emphasizing skeletal muscle hypertrophy and atrophy across cellular and animal models, as well as human investigations. In addition, we present working mechanistic theories for heat shock protein-mediated signaling effects regarding hypertrophy and atrophy-related signaling processes. Importantly, continued research is necessary to determine the practical effects and mechanisms of heat stress with and without resistance exercise on skeletal muscle function via growth and maintenance.
Topics: Animals; Atrophy; Exercise; Heat-Shock Proteins; Heat-Shock Response; Hypertrophy; Muscle, Skeletal; Muscular Atrophy
PubMed: 35536704
DOI: 10.1152/ajpregu.00048.2022