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Scientific Reports Sep 2023The heart depends on a functional vasculature for oxygenation and transport of nutrients, and it is of interest to learn how primary impairment of the vasculature can...
The heart depends on a functional vasculature for oxygenation and transport of nutrients, and it is of interest to learn how primary impairment of the vasculature can indirectly affect cardiac function and heart morphology. Notch3-deficiency causes vascular smooth muscle cell (VSMC) loss in the vasculature but the consequences for the heart remain largely elusive. Here, we demonstrate that Notch3 mice have enlarged hearts with left ventricular hypertrophy and mild fibrosis. Cardiomyocytes were hypertrophic but not hyperproliferative, and the expression of several cardiomyocyte markers, including Tnt2, Myh6, Myh7 and Actn2, was altered. Furthermore, expression of genes regulating the metabolic status of the heart was affected: both Pdk4 and Cd36 were downregulated, indicating a metabolic switch from fatty acid oxidation to glucose consumption. Notch3 mice furthermore showed lower liver lipid content. Notch3 was expressed in heart VSMC and pericytes but not in cardiomyocytes, suggesting that a perturbation of Notch signalling in VSMC and pericytes indirectly impairs the cardiomyocytes. In keeping with this, Pdgfb mice, characterized by reduced numbers of VSMC and pericytes, showed left ventricular and cardiomyocyte hypertrophy. In conclusion, we demonstrate that reduced Notch3 or PDGFB signalling in vascular mural cells leads to cardiomyocyte dysfunction.
Topics: Animals; Mice; Becaplermin; Cardiomegaly; Hypertrophy, Left Ventricular; Lipid Metabolism; Myocytes, Cardiac; Proto-Oncogene Proteins c-sis
PubMed: 37699967
DOI: 10.1038/s41598-023-42010-7 -
Physiological Reports Oct 2022Skeletal muscle is a plastic tissue that regenerates ad integrum after injury and adapts to raise mechanical loading/contractile activity by increasing its mass and/or... (Review)
Review
Skeletal muscle is a plastic tissue that regenerates ad integrum after injury and adapts to raise mechanical loading/contractile activity by increasing its mass and/or myofiber size, a phenomenon commonly refers to as skeletal muscle hypertrophy. Both muscle regeneration and hypertrophy rely on the interactions between muscle stem cells and their neighborhood, which include inflammatory cells, and particularly macrophages. This review first summarizes the role of macrophages in muscle regeneration in various animal models of injury and in response to exercise-induced muscle damage in humans. Then, the potential contribution of macrophages to skeletal muscle hypertrophy is discussed on the basis of both animal and human experiments. We also present a brief comparative analysis of the role of macrophages during muscle regeneration versus hypertrophy. Finally, we summarize the current knowledge on the impact of different immunomodulatory strategies, such as heat therapy, cooling, massage, nonsteroidal anti-inflammatory drugs and resolvins, on skeletal muscle regeneration and their potential impact on muscle hypertrophy.
Topics: Animals; Anti-Inflammatory Agents; Humans; Hypertrophy; Macrophages; Muscle, Skeletal; Plastics; Regeneration
PubMed: 36200266
DOI: 10.14814/phy2.15480 -
International Journal of Molecular... Nov 2022Oxidative stress and inflammation are associated with skeletal muscle function decline with ageing or disease or inadequate exercise and/or poor diet. Paradoxically,... (Review)
Review
Oxidative stress and inflammation are associated with skeletal muscle function decline with ageing or disease or inadequate exercise and/or poor diet. Paradoxically, reactive oxygen species and inflammatory cytokines are key for mounting the muscular and systemic adaptive responses to endurance and resistance exercise. Both ageing and lifestyle-related metabolic dysfunction are strongly linked to exercise redox and hypertrophic insensitivity. The adaptive inability and consequent exercise intolerance may discourage people from physical training resulting in a vicious cycle of under-exercising, energy surplus, chronic mitochondrial stress, accelerated functional decline and increased susceptibility to serious diseases. Skeletal muscles are malleable and dynamic organs, rewiring their metabolism depending on the metabolic or mechanical stress resulting in a specific phenotype. Endogenous RNA silencing molecules, microRNAs, are regulators of these metabolic/phenotypic shifts in skeletal muscles. Skeletal muscle microRNA profiles at baseline and in response to exercise have been observed to differ between adult and older people, as well as trained vs. sedentary individuals. Likewise, the circulating microRNA blueprint varies based on age and training status. Therefore, microRNAs emerge as key regulators of metabolic health/capacity and hormetic adaptability. In this narrative review, we summarise the literature exploring the links between microRNAs and skeletal muscle, as well as systemic adaptation to exercise. We expand a mathematical model of microRNA burst during adaptation to exercise through supporting data from the literature. We describe a potential link between the microRNA-dependent regulation of redox-signalling sensitivity and the ability to mount a hypertrophic response to exercise or nutritional cues. We propose a hypothetical model of endurance exercise-induced microRNA "memory cloud" responsible for establishing a landscape conducive to aerobic as well as anabolic adaptation. We suggest that regular aerobic exercise, complimented by a healthy diet, in addition to promoting mitochondrial health and hypertrophic/insulin sensitivity, may also suppress the glycolytic phenotype and mTOR signalling through miRNAs which in turn promote systemic metabolic health.
Topics: Humans; MicroRNAs; Muscle, Skeletal; Exercise; Circulating MicroRNA; Signal Transduction; Hypertrophy
PubMed: 36499053
DOI: 10.3390/ijms232314716 -
The Journal of Physiology Jun 2023Considerable inter-individual heterogeneity exists in the muscular adaptations to resistance training. It has been proposed that fast-twitch fibres are more sensitive to...
Considerable inter-individual heterogeneity exists in the muscular adaptations to resistance training. It has been proposed that fast-twitch fibres are more sensitive to hypertrophic stimuli and thus that variation in muscle fibre type composition is a contributing factor to the magnitude of training response. This study investigated if the inter-individual variability in resistance training adaptations is determined by muscle typology and if the most appropriate weekly training frequency depends on muscle typology. In strength-training novices, 11 slow (ST) and 10 fast typology (FT) individuals were selected by measuring muscle carnosine with proton magnetic resonance spectroscopy. Participants trained both upper arm and leg muscles to failure at 60% of one-repetition maximum (1RM) for 10 weeks, whereby one arm and leg trained 3×/week and the contralateral arm and leg 2×/week. Muscle volume (MRI-based 3D segmentation), maximal dynamic strength (1RM) and fibre type-specific cross-sectional area (vastus lateralis biopsies) were evaluated. The training response for total muscle volume (+3 to +14%), fibre size (-19 to +22%) and strength (+17 to +47%) showed considerable inter-individual variability, but these could not be attributed to differences in muscle typology. However, ST individuals performed a significantly higher training volume to gain these similar adaptations than FT individuals. The limb that trained 3×/week had generally more pronounced hypertrophy than the limb that trained 2×/week, and there was no interaction with muscle typology. In conclusion, muscle typology cannot explain the high variability in resistance training adaptations when training is performed to failure at 60% of 1RM. KEY POINTS: This study investigated the influence of muscle typology (muscle fibre type composition) on the variability in resistance training adaptations and on its role in the individualization of resistance training frequency. We demonstrate that an individual's muscle typology cannot explain the inter-individual variability in resistance training-induced increases in muscle volume, maximal dynamic strength and fibre cross-sectional area when repetitions are performed to failure. Importantly, slow typology individuals performed a significantly higher training volume to obtain similar adaptations compared to fast typology individuals. Muscle typology does not determine the most appropriate resistance training frequency. However, regardless of muscle typology, an additional weekly training (3×/week vs. 2×/week) increases muscle hypertrophy but not maximal dynamic strength. These findings expand on our understanding of the underlying mechanisms for the large inter-individual variability in resistance training adaptations.
Topics: Humans; Resistance Training; Muscle, Skeletal; Muscle Fibers, Skeletal; Quadriceps Muscle; Adaptation, Physiological; Hypertrophy; Muscle Strength
PubMed: 37038845
DOI: 10.1113/JP284442 -
Bioscience Reports Dec 2019Pathological cardiac hypertrophy is a complex process and eventually develops into heart failure, in which the heart responds to various intrinsic or external stress,... (Review)
Review
Pathological cardiac hypertrophy is a complex process and eventually develops into heart failure, in which the heart responds to various intrinsic or external stress, involving increased interstitial fibrosis, cell death and cardiac dysfunction. Studies have shown that oxidative stress is an important mechanism for this maladaptation. Cyclophilin A (CyPA) is a member of the cyclophilin (CyPs) family. Many cells secrete CyPA to the outside of the cells in response to oxidative stress. CyPA from blood vessels and the heart itself participate in a variety of signaling pathways to regulate the production of reactive oxygen species (ROS) and mediate inflammation, promote cardiomyocyte hypertrophy and proliferation of cardiac fibroblasts, stimulate endothelial injury and vascular smooth muscle hyperplasia, and promote the dissolution of extracellular matrix (ECM) by activating matrix metalloproteinases (MMPs). The events triggered by CyPA cause a decline of diastolic and systolic function and finally lead to the occurrence of heart failure. This article aims to introduce the role and mechanism of CyPA in cardiac hypertrophy and remodeling, and highlights its potential role as a disease biomarker and therapeutic target.
Topics: Animals; Cardiomegaly; Collagenases; Cyclophilin A; Extracellular Matrix; Fibroblasts; Heart Failure; Humans; Myocardium; Oxidative Stress; Reactive Oxygen Species; Ventricular Remodeling
PubMed: 31825469
DOI: 10.1042/BSR20193190 -
International Journal of Molecular... Jun 2022With aging, sarcopenia and the associated locomotor disorders, have become serious problems. The roots of maca contain active ingredients (triterpenes) that have a...
With aging, sarcopenia and the associated locomotor disorders, have become serious problems. The roots of maca contain active ingredients (triterpenes) that have a preventive effect on sarcopenia. However, the effect of maca on muscle hypertrophy has not yet been investigated. The aim of this study was to examine the effects and mechanism of maca on muscle hypertrophy by adding different concentrations of yellow maca (0.1 mg/mL and 0.2 mg/mL) to C2C12 skeletal muscle cell culture. Two days after differentiation, maca was added for two days of incubation. The muscle diameter, area, differentiation index, and multinucleation, were assessed by immunostaining, and the expression levels of the proteins related to muscle protein synthesis/degradation were examined by Western blotting. Compared with the control group, the muscle diameter and area of the myotubes in the maca groups were significantly increased, and the cell differentiation index and multinucleation were significantly higher in the maca groups. Phosphorylation of Akt and mTOR was elevated in the maca groups. Maca also promoted the phosphorylation of AMPK. These results suggest that maca may promote muscle hypertrophy, differentiation, and maturation, potentially via the muscle hypertrophic signaling pathways such as Akt and mTOR, while exploring other pathways are needed.
Topics: Hypertrophy; Lepidium; Muscle Fibers, Skeletal; Muscle, Skeletal; Proto-Oncogene Proteins c-akt; Sarcopenia; TOR Serine-Threonine Kinases
PubMed: 35743270
DOI: 10.3390/ijms23126825 -
Cardiovascular Research Mar 2023Blood eosinophil (EOS) counts and EOS cationic protein (ECP) levels associate positively with major cardiovascular disease (CVD) risk factors and prevalence. This study...
AIMS
Blood eosinophil (EOS) counts and EOS cationic protein (ECP) levels associate positively with major cardiovascular disease (CVD) risk factors and prevalence. This study investigates the role of EOS in cardiac hypertrophy.
METHODS AND RESULTS
A retrospective cross-section study of 644 consecutive inpatients with hypertension examined the association between blood EOS counts and cardiac hypertrophy. Pressure overload- and β-adrenoreceptor agonist isoproterenol-induced cardiac hypertrophy was produced in EOS-deficient ΔdblGATA mice. This study revealed positive correlations between blood EOS counts and left ventricular (LV) mass and mass index in humans. ΔdblGATA mice showed exacerbated cardiac hypertrophy and dysfunction, with increased LV wall thickness, reduced LV internal diameter, and increased myocardial cell size, death, and fibrosis. Repopulation of EOS from wild-type (WT) mice, but not those from IL4-deficient mice ameliorated cardiac hypertrophy and cardiac dysfunctions. In ΔdblGATA and WT mice, administration of ECP mEar1 improved cardiac hypertrophy and function. Mechanistic studies demonstrated that EOS expression of IL4, IL13, and mEar1 was essential to control mouse cardiomyocyte hypertrophy and death and cardiac fibroblast TGF-β signalling and fibrotic protein synthesis. The use of human cardiac cells yielded the same results. Human ECP, EOS-derived neurotoxin, human EOS, or murine recombinant mEar1 reduced human cardiomyocyte death and hypertrophy and human cardiac fibroblast TGF-β signalling.
CONCLUSION
Although blood EOS counts correlated positively with LV mass or LV mass index in humans, this study established a cardioprotective role for EOS IL4 and cationic proteins in cardiac hypertrophy and tested a therapeutic possibility of ECPs in this human CVD.
Topics: Mice; Humans; Animals; Hypertrophy, Left Ventricular; Eosinophils; Retrospective Studies; Interleukin-4; Cardiomegaly; Myocytes, Cardiac; Adrenergic beta-Agonists; Transforming Growth Factor beta; Fibrosis; Ventricular Remodeling
PubMed: 35394031
DOI: 10.1093/cvr/cvac060 -
Matrix Biology : Journal of the... Feb 2022The regulation of skeletal muscle growth following pro-hypertrophic stimuli requires a coordinated response by different cell types that leads to extracellular matrix...
The regulation of skeletal muscle growth following pro-hypertrophic stimuli requires a coordinated response by different cell types that leads to extracellular matrix (ECM) remodeling and increases in muscle cross-sectional area. Indeed, matricellular proteins serve a key role as communication vehicles that facilitate the propagation of signaling stimuli required for muscle adaptation to environmental challenges. We found that the matricellular protein cellular communication network factor 2 (CCN2), also known as connective tissue growth factor (CTGF), is induced during a time course of overload-driven skeletal muscle hypertrophy in mice. To elucidate the role of CCN2 in mediating the hypertrophic response, we utilized genetically engineered mouse models for myofiber-specific CCN2 gain- and loss-of-function and then examined their response to mechanical stimuli through muscle overload. Interestingly, myofiber-specific deletion of CCN2 blunted muscle's hypertrophic response to overload without interfering with ECM deposition. On the other hand, when in excess through transgenic CCN2 overexpression, CCN2 was efficient in promoting overload-induced aberrant ECM accumulation without affecting myofiber growth. Altogether, our genetic approaches highlighted independent ECM and myofiber stress adaptation responses, and positioned CCN2 as a central mediator of both. Mechanistically, CCN2 acts by regulating focal adhesion kinase (FAK) mediated transduction of overload-induced extracellular signals, including interleukin 6 (IL6), and their regulatory impact on global protein synthesis in skeletal muscle. Overall, our study highlights the contribution of muscle-derived extracellular matrix factor CCN2 for proper hypertrophic muscle growth.
Topics: Animals; Connective Tissue Growth Factor; Extracellular Matrix; Hypertrophy; Mice; Muscle, Skeletal; Signal Transduction
PubMed: 35045313
DOI: 10.1016/j.matbio.2022.01.003 -
Cell Stem Cell Feb 2022Adaptation to mechanical load, leading to enhanced force and power output, is a characteristic feature of skeletal muscle. Formation of new myonuclei required for...
Adaptation to mechanical load, leading to enhanced force and power output, is a characteristic feature of skeletal muscle. Formation of new myonuclei required for efficient muscle hypertrophy relies on prior activation and proliferation of muscle stem cells (MuSCs). However, the mechanisms controlling MuSC expansion under conditions of increased load are not fully understood. Here we demonstrate that interstitial mesenchymal progenitors respond to mechanical load and stimulate MuSC proliferation in a surgical mouse model of increased muscle load. Mechanistically, transcriptional activation of Yes-associated protein 1 (Yap1)/transcriptional coactivator with PDZ-binding motif (Taz) in mesenchymal progenitors results in local production of thrombospondin-1 (Thbs1), which, in turn, drives MuSC proliferation through CD47 signaling. Under homeostatic conditions, however, CD47 signaling is insufficient to promote MuSC proliferation and instead depends on prior downregulation of the Calcitonin receptor. Our results suggest that relayed signaling between mesenchymal progenitors and MuSCs through a Yap1/Taz-Thbs1-CD47 pathway is critical to establish the supply of MuSCs during muscle hypertrophy.
Topics: Animals; CD47 Antigen; Hypertrophy; Mice; Muscle, Skeletal; Myoblasts; Stem Cells
PubMed: 34856120
DOI: 10.1016/j.stem.2021.11.003 -
STAR Protocols Mar 2022The skeletal muscle system is the major organ associated with movement of the body. Myogenesis and regeneration induced post-injury contribute to muscle formation and...
The skeletal muscle system is the major organ associated with movement of the body. Myogenesis and regeneration induced post-injury contribute to muscle formation and maintenance. Here, we provide detailed protocol for the accelerated repair of injured skeletal muscles and generation of hypertrophic muscle fibers. This protocol includes cardiotoxin induced muscle injury and also describes isolation of satellite cells from skeletal muscle tissues of mice. This protocol can be used to study the mechanisms associated with accelerated muscle repair and hypertrophy. For complete details on the use and execution of this protocol, please refer to Ray et al. (2021).
Topics: Animals; Hypertrophy; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Muscular Diseases; Regeneration
PubMed: 35118424
DOI: 10.1016/j.xpro.2021.101111