scholarly journals Myosin Heavy Chain-embryonic is a crucial regulator of skeletal muscle development and differentiation

2018 ◽  
Author(s):  
Akashi Sharma ◽  
Megha Agarwal ◽  
Amit Kumar ◽  
Pankaj Kumar ◽  
Masum Saini ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Development ◽  
Myogenic Differentiation ◽  
Fiber Type ◽  
Mitogen Activated Protein Kinase ◽  
Myoblast Differentiation ◽  
Loss Of Function ◽  
Heavy Chains ◽  
Mitogen Activated Protein ◽  
Fiber Number

SummaryMyosin heavy chains (MyHCs) are contractile proteins that are part of the thick filaments of the functional unit of the skeletal muscle, the sarcomere. In addition to MyHCs that are part of the adult muscle contractile network, two MyHCs - MyHC-embryonic and -perinatal are expressed during muscle development and are only transiently expressed in the adult during regeneration. The functions performed by these MyHCs has been a long-standing question and using a targeted mouse allele, we have characterized the role of MyHC-embryonic. Analysis of loss-of-function mice reveals that lack of MyHC-embryonic leads to mis-regulation of other MyHCs, alterations in fiber size, fiber number and fiber type at neonatal stages. We also find that loss of MyHC-embryonic leads to mis-regulation of genes involved in muscle differentiation. A broad theme from these studies is that loss of MyHC-embryonic has distinct effects on different muscles, possibly reflecting the unique fiber type composition of different muscles. Most significantly, our results indicate that MyHC-embryonic is required during embryonic and fetal myogenesis to regulate myogenic progenitor and myoblast differentiation in a non-cell autonomous manner via Mitogen Activated Protein Kinase (MAPKinase) and Fibroblast Growth Factor (FGF) signaling. Thus, our results signify that MyHC-embryonic is a key regulator of myogenic differentiation during embryonic, fetal and neonatal myogenesis.

scholarly journals Hsp70 Interacts with Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 To Regulate p38MAPK Stability and Myoblast Differentiation during Skeletal Muscle Regeneration

2018 ◽  
Vol 38 (24) ◽  
Author(s):  
Wei Fan ◽  
Xiu Kui Gao ◽  
Xi Sheng Rao ◽  
Yin Pu Shi ◽  
Xiao Ceng Liu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Muscle Regeneration ◽  
Myogenic Differentiation ◽  
Regenerative Process ◽  
Mitogen Activated Protein Kinase ◽  
Skeletal Muscle Regeneration ◽  
Myoblast Differentiation ◽  
Mitogen Activated Protein ◽  
The Stability

ABSTRACT The regenerative process of injured muscle is dependent on the fusion and differentiation of myoblasts derived from muscle stem cells. Hsp70 is important for maintaining skeletal muscle homeostasis and regeneration, but the precise cellular mechanism remains elusive. In this study, we found that Hsp70 was upregulated during myoblast differentiation. Depletion or inhibition of Hsp70/Hsc70 impaired myoblast differentiation. Importantly, overexpression of p38 mitogen-activated protein kinase α (p38MAPKα) but not AKT1 rescued the impairment of myogenic differentiation in Hsp70- or Hsc70-depleted myoblasts. Moreover, Hsp70 interacted with MK2, a substrate of p38MAPK, to regulate the stability of p38MAPK. Knockdown of Hsp70 also led to downregulation of both MK2 and p38MAPK in intact muscles and during cardiotoxin-induced muscle regeneration. Hsp70 bound MK2 to regulate MK2-p38MAPK interaction in myoblasts. We subsequently identified the essential regions required for Hsp70-MK2 interaction. Functional analyses showed that MK2 is essential for both myoblast differentiation and skeletal muscle regeneration. Taken together, our findings reveal a novel role of Hsp70 in regulating myoblast differentiation by interacting with MK2 to stabilize p38MAPK.

scholarly journals A Cdo–Bnip-2–Cdc42 signaling pathway regulates p38α/β MAPK activity and myogenic differentiation

2008 ◽  
Vol 182 (3) ◽  
pp. 497-507 ◽  
Author(s):  
Jong-Sun Kang ◽  
Gyu-Un Bae ◽  
Min-Jeong Yi ◽  
Youn-Joo Yang ◽  
Ji-Eun Oh ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Surface ◽  
Mapk Pathway ◽  
Myogenic Differentiation ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Cell Surface Receptor ◽  
Myoblast Differentiation ◽  
Loss Of Function ◽  
Surface Receptor

The p38α/β mitogen-activated protein kinase (MAPK) pathway promotes skeletal myogenesis, but the mechanisms by which it is activated during this process are unclear. During myoblast differentiation, the promyogenic cell surface receptor Cdo binds to the p38α/β pathway scaffold protein JLP and, via JLP, p38α/β itself. We report that Cdo also interacts with Bnip-2, a protein that binds the small guanosine triphosphatase (GTPase) Cdc42 and a negative regulator of Cdc42, Cdc42 GTPase-activating protein (GAP). Moreover, Bnip-2 and JLP are brought together through mutual interaction with Cdo. Gain- and loss-of-function experiments with myoblasts indicate that the Cdo–Bnip-2 interaction stimulates Cdc42 activity, which in turn promotes p38α/β activity and cell differentiation. These results reveal a previously unknown linkage between a cell surface receptor and downstream modulation of Cdc42 activity. Furthermore, interaction with multiple scaffold-type proteins is a distinctive mode of cell surface receptor signaling and provides one mechanism for specificity of p38α/β activation during cell differentiation.

scholarly journals KDM4A regulates myogenesis by demethylating H3K9me3 of myogenic regulatory factors

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Qi Zhu ◽  
Feng Liang ◽  
Shufang Cai ◽  
Xiaorong Luo ◽  
Tianqi Duo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Proliferation ◽  
Satellite Cells ◽  
Muscle Development ◽  
Kinase Inhibitor ◽  
Myogenic Differentiation ◽  
Myoblast Differentiation ◽  
Proliferation And Differentiation ◽  
H3k9me3 Level

AbstractHistone lysine demethylase 4A (KDM4A) plays a crucial role in regulating cell proliferation, cell differentiation, development and tumorigenesis. However, little is known about the function of KDM4A in muscle development and regeneration. Here, we found that the conditional ablation of KDM4A in skeletal muscle caused impairment of embryonic and postnatal muscle formation. The loss of KDM4A in satellite cells led to defective muscle regeneration and blocked the proliferation and differentiation of satellite cells. Myogenic differentiation and myotube formation in KDM4A-deficient myoblasts were inhibited. Chromatin immunoprecipitation assay revealed that KDM4A promoted myogenesis by removing the histone methylation mark H3K9me3 at MyoD, MyoG and Myf5 locus. Furthermore, inactivation of KDM4A in myoblasts suppressed myoblast differentiation and accelerated H3K9me3 level. Knockdown of KDM4A in vitro reduced myoblast proliferation through enhancing the expression of the cyclin-dependent kinase inhibitor P21 and decreasing the expression of cell cycle regulator Cyclin D1. Together, our findings identify KDM4A as an important regulator for skeletal muscle development and regeneration, orchestrating myogenic cell proliferation and differentiation.

scholarly journals BDNF is a mediator of glycolytic fiber-type specification in mouse skeletal muscle

2019 ◽  
Vol 116 (32) ◽  
pp. 16111-16120 ◽  
Author(s):  
Julien Delezie ◽  
Martin Weihrauch ◽  
Geraldine Maier ◽  
Rocío Tejero ◽  
Daniel J. Ham ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Morphological Changes ◽  
Fiber Type ◽  
Slow Muscle ◽  
Loss Of Function ◽  
Muscle Type ◽  
Fiber Number ◽  
Type Gene ◽  
Type Specification

Brain-derived neurotrophic factor (BDNF) influences the differentiation, plasticity, and survival of central neurons and likewise, affects the development of the neuromuscular system. Besides its neuronal origin, BDNF is also a member of the myokine family. However, the role of skeletal muscle-derived BDNF in regulating neuromuscular physiology in vivo remains unclear. Using gain- and loss-of-function animal models, we show that muscle-specific ablation of BDNF shifts the proportion of muscle fibers from type IIB to IIX, concomitant with elevated slow muscle-type gene expression. Furthermore, BDNF deletion reduces motor end plate volume without affecting neuromuscular junction (NMJ) integrity. These morphological changes are associated with slow muscle function and a greater resistance to contraction-induced fatigue. Conversely, BDNF overexpression promotes a fast muscle-type gene program and elevates glycolytic fiber number. These findings indicate that BDNF is required for fiber-type specification and provide insights into its potential modulation as a therapeutic target in muscle diseases.

scholarly journals Akt Phosphorylation Is Not Sufficient for Insulin-Like Growth Factor-Stimulated Myogenin Expression but Must Be Accompanied by Down-Regulation of Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Phosphorylation

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 4991-4996 ◽  
Author(s):  
Nicki Tiffin ◽  
Saleh Adi ◽  
David Stokoe ◽  
Nan-Yan Wu ◽  
Stephen M. Rosenthal
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Myogenic Differentiation ◽  
Mitogen Activated Protein Kinase ◽  
Response To Treatment ◽  
Akt Phosphorylation ◽  
Extracellular Signal ◽  
Phosphorylated Akt ◽  
Igf I ◽  
Mitogen Activated Protein

Abstract IGF-I has a unique biphasic effect on skeletal muscle differentiation. Initially, IGF-I inhibits expression of myogenin, a skeletal muscle-specific regulatory factor essential for myogenesis. Subsequently, IGF-I switches to stimulating expression of myogenin. The mechanisms that mediate this switch in IGF action are incompletely understood. Several laboratories have demonstrated that the phosphatidylinositol-3-kinase/Akt signaling pathway is essential for myogenic differentiation and have suggested that this pathway mediates IGF-I stimulation of myogenin mRNA expression, an early critical step in the differentiation process. These studies, however, did not address concurrent Akt and MAPK/ERK1/2 phosphorylation, the latter of which is also known to regulate myogenic differentiation. In the present study in rat L6E9 muscle cells, we have manipulated ERK1/2 phosphorylation with either an upstream inhibitor or activator and examined concurrent levels of Akt and ERK1/2 phosphorylation and of myogenin mRNA expression in response to treatment with IGF-I. We find that even in the presence of phosphorylated Akt, it is only when ERK1/2 phosphorylation is inhibited that IGF-I can stimulate myogenin mRNA expression. Thus, although Akt phosphorylation may be necessary, it is not sufficient for induction of myogenic differentiation by IGF-I and must be accompanied by a decrease in ERK1/2 phosphorylation.

scholarly journals The histone methyltransferase Set7/9 promotes myoblast differentiation and myofibril assembly

2011 ◽  
Vol 194 (4) ◽  
pp. 551-565 ◽  
Author(s):  
Yazhong Tao ◽  
Ronald L. Neppl ◽  
Zhan-Peng Huang ◽  
Jianfu Chen ◽  
Ru-Hang Tang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Development ◽  
Myogenic Differentiation ◽  
Muscle Differentiation ◽  
Histone Methyltransferase ◽  
Contractile Proteins ◽  
Dominant Negative ◽  
Myoblast Differentiation ◽  
Skeletal Muscle Differentiation ◽  
Muscle Gene Expression

The molecular events that modulate chromatin structure during skeletal muscle differentiation are still poorly understood. We report in this paper that expression of the H3-K4 histone methyltransferase Set7 is increased when myoblasts differentiate into myotubes and is required for skeletal muscle development, expression of muscle contractile proteins, and myofibril assembly. Knockdown of Set7 or expression of a dominant-negative Set7 mutant impairs skeletal muscle differentiation, accompanied by a decrease in levels of histone monomethylation (H3-K4me1). Set7 directly interacts with MyoD to enhance expression of muscle differentiation genes. Expression of myocyte enhancer factor 2 and genes encoding contractile proteins is decreased in Set7 knockdown myocytes. Furthermore, we demonstrate that Set7 also activates muscle gene expression by precluding Suv39h1-mediated H3-K9 methylation on the promoters of myogenic differentiation genes. Together, our experiments define a biological function for Set7 in muscle differentiation and provide a molecular mechanism by which Set7 modulates myogenic transcription factors during muscle differentiation.

Modulation of skeletal muscle fiber type by mitogen‐activated protein kinase signaling

2008 ◽  
Vol 22 (8) ◽  
pp. 2990-3000 ◽  
Author(s):  
Hao Shi ◽  
Jason M. Scheffler ◽  
Jonathan M. Pleitner ◽  
Caiyun Zeng ◽  
Sungkwon Park ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Muscle Fiber ◽  
Fiber Type ◽  
Skeletal Muscle Fiber ◽  
Muscle Fiber Type ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Signaling ◽  
Mitogen Activated Protein ◽  
Protein Kinase Signaling

scholarly journals Male-Biased gga-miR-2954 Regulates Myoblast Proliferation and Differentiation of Chicken Embryos by Targeting YY1

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1325
Author(s):  
Xiuxue Dong ◽  
Yu Cheng ◽  
Lingyun Qiao ◽  
Xin Wang ◽  
Cuiping Zeng ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Development ◽  
Expression Profiles ◽  
Myoblast Differentiation ◽  
Mammalian Skeletal Muscle ◽  
Loss Of Function ◽  
Skeletal Muscle Development ◽  
Chicken Muscle ◽  
Proliferation And Differentiation ◽  
Myoblast Proliferation

Previous studies have shown that gga-miR-2954 was highly expressed in the gonads and other tissues of male chickens, including muscle tissue. Yin Yang1 (YY1), which has functions in mammalian skeletal muscle development, was predicted to be a target gene of gga-miR-2954. The purpose of this study was to investigate whether gga-miR-2954 plays a role in skeletal muscle development by targeting YY1, and evaluate its function in the sexual dimorphism development of chicken muscle. Here, all the temporal and spatial expression profiles in chicken embryonic muscles showed that gga-miR-2954 is highly expressed in males and mainly localized in cytoplasm. Gga-miR-2954 exhibited upregulated expression of in vitro myoblast differentiation stages. Next, through the overexpression and loss-of-function experiments performed in chicken primary myoblasts, we found that gga-miR-2954 inhibited myoblast proliferation but promoted differentiation. During myogenesis, gga-miR-2954 could suppress the expression of YY1, which promoted myoblast proliferation and inhibited the process of myoblast cell differentiation into multinucleated myotubes. Overall, these findings reveal a novel role of gga-miR-2954 in skeletal muscle development through its function of the myoblast proliferation and differentiation by suppressing the expression of YY1. Moreover, gga-miR-2954 may contribute to the sex difference in chicken muscle development.

scholarly journals Mitogen-Activated Protein Kinase-Dependent Fiber-Type Regulation in Skeletal Muscle

2018 ◽  
Author(s):  
Justin G. Boyer ◽  
Taejeong Song ◽  
Donghoon Lee ◽  
Xing Fu ◽  
Sakthivel Sadayappan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinases ◽  
Fiber Type ◽  
Mouse Genetics ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Specific Expression ◽  
Mitogen Activated Protein ◽  
Similar Phenotype

AbstractMitogen-activated protein kinases (MAPK) are conserved protein kinases that regulate a diverse array of cellular activities. Stress or mitogenic signals activate three primary branches of the greater MAPK cascade, each of which consists of a phosphorylation-dependent array of successively acting kinases. The extracellular signal-regulated kinase 1/2 (ERK1/2) branch is regulated by growth factory signaling at the cell membrane, leading to phosphorylation of the dual-specificity kinase MEK1, which is dedicated to ERK1/2 phosphorylation. Previous studies have established a link between MAPK activation and endurance exercise, but whether a single MAPK is responsible for establishing muscle metabolic fate is unclear. Using mouse genetics we observed that muscle-specific expression of a constitutively active MEK1 promotes greater ERK1/2 signaling that mediates fiber-type switching in mouse skeletal muscle to a slow, oxidative phenotype with type I myosin heavy chain expression. Induced expression of the activated MEK1 mutant using either a MyoD-Cre or myosin light chain-Cre strategy equally increased the number of type I fibers in skeletal muscle with significantly reduced size compared to controls. Moreover, activation of MEK1 in mature myofibers of an adult mouse using a transgene containing a tamoxifen inducible MerCreMer cDNA under the control of a skeletal α-actin promoter produced a similar phenotype of switching towards a slow-oxidative program. Physiologic assessment of mice with greater skeletal muscle slow-oxidative fibers showed enhanced metabolic activity and oxygen consumption with greater fatigue resistance of individual muscles. In summary, these results show that sustained MEK1-ERK1/2 activity in skeletal muscle produces a fast-to-slow fiber-type switch, suggesting that modulation of this signaling pathway may represent a therapeutic approach to enhance the long-term metabolic effectiveness of musclein vivo.

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