Skeletal muscle, the essential organ for locomotion, as well as energy reservoir and expenditure, has robust regenerative capacity in response to mechanical stress and injury. As muscle-specific stem ...cells, satellite cells are responsible for providing new myoblasts during the process of muscle growth and regeneration. Self-renewal capacity and the fate of satellite cells are highly regulated and influenced by their surrounding factors, such as extracellular matrix and soluble proteins. The strong myogenic potential of satellite cells makes them a potential resource for stem cell therapy to cure genetic muscle disease and repair injured muscle. Here, we both review key features of satellite cells during skeletal muscle development and regeneration and summarize recent outcomes of satellite cell transplantation studies.
Essential hypertension (EH) is a multifactorial disease of the cardiovascular system that is influenced by the interplay of genetic, epigenetic, and environmental factors. The molecular dynamics ...underlying EH etiopathogenesis is unknown; however, earlier studies have revealed EH-associated genetic variants. Nevertheless, this finding alone is not sufficient to explain the variability in blood pressure, suggesting that other risk factors are involved, such as epigenetic modifications. Therefore, this review highlights the potential contribution of well-defined epigenetic mechanisms in EH, specifically, DNA methylation, post-translational histone modifications, and microRNAs. We further emphasize global and gene-specific DNA methylation as one of the most well-studied hallmarks among all epigenetic modifications in EH. In addition, post-translational histone modifications, such as methylation, acetylation, and phosphorylation, are described as important epigenetic markers associated with EH. Finally, we discuss microRNAs that affect blood pressure by regulating master genes such as those implicated in the renin-angiotensin-aldosterone system. These epigenetic modifications, which appear to contribute to various cardiovascular diseases, including EH, may be a promising research area for the development of novel future strategies for EH prevention and therapeutics.
Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) accelerates cardiac contractility. However, the mechanisms by which cMyBP-C phosphorylation increases contractile kinetics have not been ...fully elucidated. In this study, we tested the hypothesis that phosphorylation of cMyBP-C releases myosin heads from the inhibited super-relaxed state (SRX), thereby determining the fraction of myosin available for contraction. Mice with various alanine (A) or aspartic acid (D) substitutions of the three main phosphorylatable serines of cMyBP-C (serines 273, 282, and 302) were used to address the association between cMyBP-C phosphorylation and SRX. Single-nucleotide turnover in skinned ventricular preparations demonstrated that phosphomimetic cMyBP-C destabilized SRX, whereas phosphoablated cMyBP-C had a stabilizing effect on SRX. Strikingly, phosphorylation at serine 282 site was found to play a critical role in regulating the SRX. Treatment of WT preparations with protein kinase A (PKA) reduced the SRX, whereas, in nonphosphorylatable cMyBP-C preparations, PKA had no detectable effect. Mice with stable SRX exhibited reduced force production. Phosphomimetic cMyBP-C with reduced SRX exhibited increased rates of tension redevelopment and reduced binding to myosin. We also used recombinant myosin subfragment-2 to disrupt the endogenous interaction between cMyBP-C and myosin and observed a significant reduction in the population of SRX myosin. This peptide also increased force generation and rate of tension redevelopment in skinned fibers. Taken together, this study demonstrates that the phosphorylation-dependent interaction between cMyBP-C and myosin is a determinant of the fraction of myosin available for contraction. Furthermore, the binding between cMyBP-C and myosin may be targeted to improve contractile function.
Mammalian cells exhibit remarkable diversity in cell size, but the factors that regulate establishment and maintenance of these sizes remain poorly understood. This is especially true for skeletal ...muscle, comprised of syncytial myofibers that each accrue hundreds of nuclei during development. Here, we directly explore the assumed causal relationship between multinucleation and establishment of normal size through titration of myonuclear numbers during mouse neonatal development. Three independent mouse models, where myonuclear numbers were reduced by 75, 55, or 25%, led to the discovery that myonuclei possess a reserve capacity to support larger functional cytoplasmic volumes in developing myofibers. Surprisingly, the results revealed an inverse relationship between nuclei numbers and reserve capacity. We propose that as myonuclear numbers increase, the range of transcriptional return on a per nuclear basis in myofibers diminishes, which accounts for both the absolute reliance developing myofibers have on nuclear accrual to establish size, and the limits of adaptability in adult skeletal muscle.
Hypertrophic cardiomyopathy (HCM) is a common cardiac condition caused primarily by sarcomeric protein mutations with several distinct phenotypes, ranging from asymmetric septal hypertrophy, either ...with or without left ventricular outflow tract obstruction, to moderate left ventricular dilation with or without apical aneurysm formation and marked, end-stage dilation with refractory heart failure. Sudden cardiac death can occur at any stage. The phenotypic variability observed in HCM is the end-result of many factors, including pre-load, after-load, wall stress and myocardial ischemia stemming from microvascular dysfunction and thrombosis; however, tissue level inflammation to include leukocyte-derived extracellular traps consisting of chromatin and histones, apoptosis, proliferation of matrix proteins and impaired or dysfunctional regulatory pathways contribute as well. Our current understanding of the pathobiology, developmental stages, transition from hypertrophy to dilation and natural history of HCM with emphasis on the role of tissue-level inflammation in myocardial fibrosis and ventricular remodeling is summarized.
Skeletal muscle adapts to external stimuli such as increased work. Muscle progenitors (MPs) control muscle repair due to severe damage, but the role of MP fusion and associated myonuclear accretion ...during exercise are unclear. While we previously demonstrated that MP fusion is required for growth using a supra-physiological model (Goh and Millay, 2017), questions remained about the need for myonuclear accrual during muscle adaptation in a physiological setting. Here, we developed an 8 week high-intensity interval training (HIIT) protocol and assessed the importance of MP fusion. In 8 month-old mice, HIIT led to progressive myonuclear accretion throughout the protocol, and functional muscle hypertrophy. Abrogation of MP fusion at the onset of HIIT resulted in exercise intolerance and fibrosis. In contrast, ablation of MP fusion 4 weeks into HIIT, preserved exercise tolerance but attenuated hypertrophy. We conclude that myonuclear accretion is required for different facets of exercise-induced adaptive responses, impacting both muscle repair and hypertrophic growth.
An innovative approach for cardiac regeneration following injury is to induce endogenous cardiomyocyte (CM) cell cycle re-entry. In the present study, CMs from adult rat hearts were isolated and ...transfected with cel-miR-67 (control) and rno-miR-210. A significant increase in CM proliferation and mono-nucleation were observed in miR-210 group, in addition to a reduction in CM size, multi-nucleation, and cell death. When compared to control, β-catenin and Bcl-2 were upregulated while APC (adenomatous polyposis coli), p16, and caspase-3 were downregulated in miR-210 group. In silico analysis predicted cell cycle inhibitor, APC, as a direct target of miR-210 in rodents. Moreover, compared to control, a significant increase in CM survival and proliferation were observed with siRNA-mediated inhibition of APC. Furthermore, miR-210 overexpressing C57BL/6 mice (210-TG) were used for short-term ischemia/reperfusion study, revealing smaller cell size, increased mono-nucleation, decreased multi-nucleation, and increased CM proliferation in 210-TG hearts in contrast to wild-type (NTG). Likewise, myocardial infarction (MI) was created in adult mice, echocardiography was performed, and the hearts were harvested for immunohistochemistry and molecular studies. Compared to NTG, 210-TG hearts showed a significant increase in CM proliferation, reduced apoptosis, upregulated angiogenesis, reduced infarct size, and overall improvement in cardiac function following MI. β-catenin, Bcl-2, and VEGF (vascular endothelial growth factor) were upregulated while APC, p16, and caspase-3 were downregulated in 210-TG hearts. Overall, constitutive overexpression of miR-210 rescues heart function following cardiac injury in adult mice via promoting CM proliferation, cell survival, and angiogenesis.
Key messages
MiRNA-210 transfected adult rat CMs show proliferation and reduced cell death
in vitro
.
Cell cycle inhibitor APC is a target of miR-210.
MiR-210 overexpressing (210-TG) mouse hearts show CMs cell cycle re-entry and survival post myocardial injury.
210-TG mice show significant neovascularization and angiogenic potential post myocardial infarction.
210-TG hearts show reduced infarct size following ischemic injury.
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