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Physiological Reviews Oct 2021The design of the energy metabolism system in striated muscle remains a major area of investigation. Here, we review our current understanding and emerging hypotheses... (Review)
Review
The design of the energy metabolism system in striated muscle remains a major area of investigation. Here, we review our current understanding and emerging hypotheses regarding the metabolic support of muscle contraction. Maintenance of ATP free energy, so called energy homeostasis, via mitochondrial oxidative phosphorylation is critical to sustained contractile activity, and this major design criterion is the focus of this review. Cell volume invested in mitochondria reduces the space available for generating contractile force, and this spatial balance between mitochondria acontractile elements to meet the varying sustained power demands across muscle types is another important design criterion. This is accomplished with remarkably similar mass-specific mitochondrial protein composition across muscle types, implying that it is the organization of mitochondria within the muscle cell that is critical to supporting sustained muscle function. Beyond the production of ATP, ubiquitous distribution of ATPases throughout the muscle requires rapid distribution of potential energy across these large cells. Distribution of potential energy has long been thought to occur primarily through facilitated metabolite diffusion, but recent analysis has questioned the importance of this process under normal physiological conditions. Recent structural and functional studies have supported the hypothesis that the mitochondrial reticulum provides a rapid energy distribution system via the conduction of the mitochondrial membrane potential to maintain metabolic homeostasis during contractile activity. We extensively review this aspect of the energy metabolism design contrasting it with metabolite diffusion models and how mitochondrial structure can play a role in the delivery of energy in the striated muscle.
Topics: Animals; Energy Metabolism; Humans; Mitochondria, Muscle; Muscle Cells; Muscle, Striated
PubMed: 33733879
DOI: 10.1152/physrev.00040.2020 -
Molecular Aspects of Medicine Apr 2018Research into the biology of extracellular vesicles (EVs), including exosomes and microvesicles, has expanded significantly with advances in EV isolation techniques, a... (Review)
Review
Research into the biology of extracellular vesicles (EVs), including exosomes and microvesicles, has expanded significantly with advances in EV isolation techniques, a better understanding of the surface markers that characterize exosomes and microvesicles, and greater information derived from -omics approaches on the proteins, lipids, mRNAs, and microRNAs (miRNAs) transported by EVs. We have recently discovered a role for exosome-derived miRNAs in age-related bone loss and osteoarthritis, two conditions that impose a significant public health burden on the aging global population. Previous work has also revealed multiple roles for EVs and their miRNAs in muscle regeneration and congenital myopathies. Thus, EVs appear to be involved in a number of degenerative conditions that impact the musculoskeletal system, indicating that the musculoskeletal system is an excellent model for investigating the role of EVs in tissue maintenance and repair. This review highlights the role of EVs in bone, skeletal muscle, and joint health, including both normal tissue metabolism as well as tissue injury repair and regeneration. A consistent theme that emerges from study of musculoskeletal EVs is that various miRNAs appear to mediate a number of key pathological processes. These findings point to a potential therapeutic opportunity to target EV-derived miRNAs as a strategy for improving musculoskeletal function.
Topics: Animals; Biomarkers; Bone and Bones; Cell Differentiation; Disease Susceptibility; Extracellular Vesicles; Humans; Joint Diseases; Muscle Cells; Musculoskeletal Diseases; Osteoporosis; Regeneration
PubMed: 28965750
DOI: 10.1016/j.mam.2017.09.006 -
Cardiovascular Research Sep 2014After a period of relative senescence in the field of vascular smooth muscle cell (VSMC) research with particular regards to atherosclerosis, the last few years has... (Review)
Review
After a period of relative senescence in the field of vascular smooth muscle cell (VSMC) research with particular regards to atherosclerosis, the last few years has witnessed a resurgence, with extensive research re-assessing potential molecular mechanisms and pathways that modulate VSMC behaviour within the atherosclerotic-prone vessel wall and the atherosclerotic plaque itself. Attention has focussed on the pathological contribution of VSMC in plaque calcification; systemic and local mediators such as inflammatory molecules and lipoproteins; autocrine and paracrine regulators which affect cell-cell and cell to matrix contacts alongside cytoskeletal changes. In this brief focused review, recent insights that have been gained into how a myriad of recently identified factors can influence the pathological behaviour of VSMC and their subsequent contribution to atherosclerotic plaque development and progression has been discussed. An overriding theme is the mechanisms involved in the alterations of VSMC function during atherosclerosis.
Topics: Animals; Atherosclerosis; Cardiovascular Physiological Phenomena; Disease Progression; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Plaque, Atherosclerotic
PubMed: 25053639
DOI: 10.1093/cvr/cvu171 -
FASEB Journal : Official Publication of... Nov 2021Kabuki syndrome (KS) is a rare genetic disorder caused primarily by mutations in the histone modifier genes KMT2D and KDM6A. The genes have broad temporal and spatial...
Kabuki syndrome (KS) is a rare genetic disorder caused primarily by mutations in the histone modifier genes KMT2D and KDM6A. The genes have broad temporal and spatial expression in many organs, resulting in complex phenotypes observed in KS patients. Hypotonia is one of the clinical presentations associated with KS, yet detailed examination of skeletal muscle samples from KS patients has not been reported. We studied the consequences of loss of KMT2D function in both mouse and human muscles. In mice, heterozygous loss of Kmt2d resulted in reduced neuromuscular junction (NMJ) perimeter, decreased muscle cell differentiation in vitro and impaired myofiber regeneration in vivo. Muscle samples from KS patients of different ages showed presence of increased fibrotic tissue interspersed between myofiber fascicles, which was not seen in mouse muscles. Importantly, when Kmt2d-deficient muscle stem cells were transplanted in vivo in a physiologic non-Kabuki environment, their differentiation potential is restored to levels undistinguishable from control cells. Thus, the epigenetic changes due to loss of function of KMT2D appear reversible through a change in milieu, opening a potential therapeutic avenue.
Topics: Abnormalities, Multiple; Adolescent; Animals; Cell Differentiation; Child; Child, Preschool; DNA-Binding Proteins; Disease Models, Animal; Face; Female; Hematologic Diseases; Histone-Lysine N-Methyltransferase; Humans; Infant; Male; Mice; Mice, Transgenic; Muscle Cells; Muscle Fibers, Skeletal; Mutation; Myeloid-Lymphoid Leukemia Protein; Neoplasm Proteins; Neuromuscular Junction; Signal Transduction; Vestibular Diseases
PubMed: 34613626
DOI: 10.1096/fj.202100823R -
Biomolecules Oct 2021(Ashwagandha) is used in Indian traditional medicine, Ayurveda, and is believed to have a variety of health-promoting effects. The molecular mechanisms and pathways...
(Ashwagandha) is used in Indian traditional medicine, Ayurveda, and is believed to have a variety of health-promoting effects. The molecular mechanisms and pathways underlying these effects have not yet been sufficiently explored. In this study, we investigated the effect of Ashwagandha extracts and their major withanolides (withaferin A and withanone) on muscle cell differentiation using C2C12 myoblasts. We found that withaferin A and withanone and Ashwagandha extracts possessing different ratios of these active ingredients have different effects on the differentiation of C2C12. Withanone and withanone-rich extracts caused stronger differentiation of myoblasts to myotubes, deaggregation of heat- and metal-stress-induced aggregated proteins, and activation of hypoxia and autophagy pathways. Of note, the Parkinson's disease model of Drosophila that possess a neuromuscular disorder showed improvement in their flight and climbing activity, suggesting the potential of Ashwagandha withanolides for the management of muscle repair and activity.
Topics: Animals; Cell Differentiation; Cell Line; Humans; Medicine, Ayurvedic; Mice; Muscle Cells; Parkinson Disease; Plant Extracts; Withanolides
PubMed: 34680087
DOI: 10.3390/biom11101454 -
FASEB Journal : Official Publication of... Nov 2021Aging exacerbates neointimal formation by reducing apoptosis of vascular smooth muscle cells (VSMCs) and induces inflammation within vascular wall. Prep1 is a...
Aging exacerbates neointimal formation by reducing apoptosis of vascular smooth muscle cells (VSMCs) and induces inflammation within vascular wall. Prep1 is a homeodomain transcription factor which stimulates the expression of proinflammatory cytokines in aortic endothelial cell models and plays a primary role in the regulation of apoptosis. In this study, we have investigated the role of Prep1 in aorta of Prep1 hypomorphic heterozygous mice (Prep1 ) and in VSMCs, and its correlation with aging. Histological analysis from Prep1 aortas revealed a 25% reduction in medial smooth muscle cell density compared to WT animals. This result paralleled higher apoptosis, caspase 3, caspase 9 and p53 levels in Prep1 mice and lower Bcl-xL. Prep1 overexpression in VSMCs decreased apoptosis by 25% and caspase 3 and caspase 9 expression by 40% and 37%. In parallel, Bcl-xL inhibition by BH3I-1 and p53 induction by etoposide reverted the antiapoptotic effect of Prep1. Experiments performed in aorta from 18 months old WT mice showed a significant increase in Prep1, p16 , p21 and interleukin 6 (IL-6) compared to youngest animals. Similar results have been observed in H O -induced senescent VSMCs. Interestingly, the synthetic Prep1 inhibitory peptide Prep1 (54-72) reduced the antiapoptotic effects mediated by IL-6, particularly in senescent VSMCs. These results indicate that IL-6-Prep1 signaling reduces apoptosis, by modulating Bcl-xL and p53 both in murine aorta and in VSMCs. In addition, age-dependent increase in IL-6 and Prep1 in senescent VSMCs and in old mice may be involved in the aging-related vascular dysfunction.
Topics: Aging; Animals; Apoptosis; Cells, Cultured; Homeodomain Proteins; Interleukin-6; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle
PubMed: 34679197
DOI: 10.1096/fj.202100943R -
Biomaterials Apr 2021A major obstacle for using human pluripotent stem cells (hPSCs) derived vascular cells for cell therapy is the lack of simple, cost-saving, and scalable methods for cell...
A major obstacle for using human pluripotent stem cells (hPSCs) derived vascular cells for cell therapy is the lack of simple, cost-saving, and scalable methods for cell production. Here we described a simplified and chemically defined medium (AATS) for endothelial cells (ECs) and smooth muscle cells (SMCs) differentiation. AATS medium does not contain insulin, enabling the rapid and highly efficient vascular mesoderm formation through accelerating metabolic and autophagy-enhanced mesoderm induction. Transcriptome profiling confirmed that hPSC-derived ECs and SMCs in the AATS medium closely resembled primary ECs and SMCs formed in vivo. ECs appeared to adhere and grow better in the AATS medium over other cell types, which allowed the purification of CD31CD144 double-positive cells. Furthermore, the AATS medium was compatible with 3D microscaffold (MS) culture, which may facilitate large-scale bioproduction of ECs. HPSC-derived ECs and SMCs in the AATS medium exhibited strong revascularization potential in treating murine ischemic models. Our study provided a cost-effective and efficient medium system to manufacture GMP compatible, off-the-shelf ECs, and SMCs to model human diseases and vascular repair.
Topics: Animals; Cell Differentiation; Endothelial Cells; Humans; Mice; Muscle, Smooth; Myocytes, Smooth Muscle; Pluripotent Stem Cells
PubMed: 33618219
DOI: 10.1016/j.biomaterials.2021.120713 -
International Journal of Molecular... Sep 2021Vascular aging is accompanied by the fragmentation of elastic fibers and collagen deposition, leading to reduced distensibility and increased vascular stiffness. A rigid... (Review)
Review
Vascular aging is accompanied by the fragmentation of elastic fibers and collagen deposition, leading to reduced distensibility and increased vascular stiffness. A rigid artery facilitates elastin to degradation by MMPs, exposing vascular cells to greater mechanical stress and triggering signaling mechanisms that only exacerbate aging, creating a self-sustaining inflammatory environment that also promotes vascular calcification. In this review, we highlight the role of crosstalk between smooth muscle cells and the vascular extracellular matrix (ECM) and how aging promotes smooth muscle cell phenotypes that ultimately lead to mechanical impairment of aging arteries. Understanding the underlying mechanisms and the role of associated changes in ECM during aging may contribute to new approaches to prevent or delay arterial aging and the onset of cardiovascular diseases.
Topics: Aging; Animals; Extracellular Matrix; Humans; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle
PubMed: 34576337
DOI: 10.3390/ijms221810175 -
Photomedicine and Laser Surgery Nov 2016The purpose of this article was to review the molecular mechanisms of low-level laser irradiation (LLLI) preconditioning for heart cell therapy. (Review)
Review
OBJECTIVE
The purpose of this article was to review the molecular mechanisms of low-level laser irradiation (LLLI) preconditioning for heart cell therapy.
BACKGROUND DATA
Stem cell transplantation appears to offer a better alternative to cardiac regenerative therapy. Previous studies have confirmed that the application of LLLI plays a positive role in regulating stem cell proliferation and in remodeling the hostile milieu of infarcted myocardium. Greater understanding of LLLI's underlying mechanisms would be helpful in translating cell transplantation therapy into the clinic.
METHODS
Studies investigating LLLI preconditioning for cardiac regenerative therapy published up to 2015 were retrieved from library sources and Pubmed databases.
RESULTS
LLLI preconditioning stimulates proliferation and differentiation of stem cells through activation of cell proliferation signaling pathways and alteration of microRNA expression. It also could stimulate paracrine secretion of stem cells and alter cardiac cytokine expression in infarcted myocardium.
CONCLUSIONS
LLLI preconditioning provides a promising approach to maximize the efficacy of cardiac cell-based therapy. Although many studies have reported possible molecular mechanisms involved in LLLI preconditioning, the exact mechanisms are still not clearly understood.
Topics: Cell Differentiation; Cell Proliferation; Cells, Cultured; Female; Humans; Ischemic Preconditioning, Myocardial; Low-Level Light Therapy; Male; Mesenchymal Stem Cell Transplantation; Muscle Cells; Myocardial Infarction; Regeneration; Ventricular Remodeling
PubMed: 27627137
DOI: 10.1089/pho.2015.4058 -
JCI Insight May 2021Excessive proliferation of vascular smooth muscle cells (SMCs) remains a significant cause of in-stent restenosis. Integrins, which are heterodimeric transmembrane...
Excessive proliferation of vascular smooth muscle cells (SMCs) remains a significant cause of in-stent restenosis. Integrins, which are heterodimeric transmembrane receptors, play a crucial role in SMC biology by binding to the extracellular matrix protein with the actin cytoskeleton within the SMC. Integrin α9 plays an important role in cell motility and autoimmune diseases; however, its role in SMC biology and remodeling remains unclear. Herein, we demonstrate that stimulated human coronary SMCs upregulate α9 expression. Targeting α9 in stimulated human coronary SMCs, using anti-integrin α9 antibody, suppresses synthetic phenotype and inhibits SMC proliferation and migration. To provide definitive evidence, we generated an SMC-specific α9-deficient mouse strain. Genetic ablation of α9 in SMCs suppressed synthetic phenotype and reduced proliferation and migration in vitro. Mechanistically, suppressed synthetic phenotype and reduced proliferation were associated with decreased focal adhesion kinase/steroid receptor coactivator signaling and downstream targets, including phosphorylated ERK, p38 MAPK, glycogen synthase kinase 3β, and nuclear β-catenin, with reduced transcriptional activation of β-catenin target genes. Following vascular injury, SMC-specific α9-deficient mice or wild-type mice treated with murine anti-integrin α9 antibody exhibited reduced injury-induced neointimal hyperplasia at day 28 by limiting SMC migration and proliferation. Our findings suggest that integrin α9 regulates SMC biology, suggesting its potential therapeutic application in vascular remodeling.
Topics: Animals; Female; Integrin alpha Chains; Male; Mice; Mice, Transgenic; Myocytes, Smooth Muscle; Phenotype; Vascular Remodeling
PubMed: 34027892
DOI: 10.1172/jci.insight.147134