Regulation of GDF-8 signaling by the p38 MAPK

Philip, Bevin; Lu, Zhijian; Gao, Yuanfeng

doi:10.1016/j.cellsig.2004.08.003

Cited by 133 publications

(114 citation statements)

References 43 publications

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“…In this study, higher myostatin level was shown to be, in part, responsible for the muscle atrophy in Smad3-null mice. This further suggests that myostatin could signal independently of Smad3 via either Smad2 or other signaling pathways, such as p38 mitogen-activated protein kinase (MAPK), c-Jun Nterminal kinase (JNK), and phosphatidylinositol 3-kinase (PI3K) pathways as shown previously [9,[39][40][41][42]. In the present manuscript, we have provided evidence to support the critical role of Smad3 in regulation of postnatal myogenesis and SC function in mice.…”

Section: Muscle Atrophy Seen In Smad3-null Muscles Could Be Due To Insupporting

confidence: 54%

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Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

McFarlane

Vajjala

et al. 2011

Cell Res

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TGF-β and myostatin are the two most important regulators of muscle growth. Both growth factors have been shown to signal through a Smad3-dependent pathway. However to date, the role of Smad3 in muscle growth and differentiation is not investigated. Here, we demonstrate that Smad3-null mice have decreased muscle mass and pronounced skeletal muscle atrophy. Consistent with this, we also find increased protein ubiquitination and elevated levels of the ubiquitin E3 ligase MuRF1 in muscle tissue isolated from Smad3-null mice. Loss of Smad3 also led to defective satellite cell (SC) functionality. Smad3-null SCs showed reduced propensity for self-renewal, which may lead to a progressive loss of SC number. Indeed, decreased SC number was observed in skeletal muscle from Smad3-null mice showing signs of severe muscle wasting. Further in vitro analysis of primary myoblast cultures identified that Smad3-null myoblasts exhibit impaired proliferation, differentiation and fusion, resulting in the formation of atrophied myotubes. A search for the molecular mechanism revealed that loss of Smad3 results in increased myostatin expression in Smad3-null muscle and myoblasts. Given that myostatin is a negative regulator, we hypothesize that increased myostatin levels are responsible for the atrophic phenotype in Smad3-null mice. Consistent with this theory, inactivation of myostatin in Smad3-null mice rescues the muscle atrophy phenotype.

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Section: Muscle Atrophy Seen In Smad3-null Muscles Could Be Due To Insupporting

confidence: 54%

“…However, other signaling pathways including Smad2 are also shown to be involved in myostatin signaling [9,13,[39][40][41][42]. In this study, higher myostatin level was shown to be, in part, responsible for the muscle atrophy in Smad3-null mice.…”

Section: Muscle Atrophy Seen In Smad3-null Muscles Could Be Due To Inmentioning

confidence: 59%

Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

McFarlane

Vajjala

et al. 2011

Cell Res

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“…Like the other members of the TGF-h superfamily, myostatin was shown to elicit its function by regulating a TGF-h-like signaling pathway through activin type IIb (ActRIIb), activin type Ib (ActRIb), or TGF-h type I receptors (13,14), followed by activation of the R-Smads. Recently, p38 mitogen-activated protein kinase (MAPK) was reported to participate in myostatin-regulated signal transduction (15). Philip et al have provided evidence that myostatin activated p38 MAPK through the TGF-h-activated kinase 1 and this activation was independent of Smads.…”

Section: Introductionmentioning

confidence: 94%

Extracellular Signal–Regulated Kinase 1/2 Mitogen-Activated Protein Kinase Pathway Is Involved in Myostatin-Regulated Differentiation Repression

et al. 2006

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The cytokines of transforming growth factor B (TGF-B) and its superfamily members are potent regulators of tumorigenesis and multiple cellular events. Myostatin is a member of TGF-B superfamily and plays a negative role in the control of cell proliferation and differentiation. We now show that myostatin rapidly activated the extracellular signal-regulated kinase 1/2 (Erk1/2) cascade in C2C12 myoblasts. A more remarkable Erk1/2 activation stimulated by myostatin was observed in differentiating cells than proliferating cells. The results also showed that Ras was the upstream regulator and participated in myostatin-induced Erk1/2 activation because the expression of a dominant-negative Ras prevented myostatin-mediated inhibition of Erk1/2 activation and proliferation. Importantly, the myostatin-suppressed myotube fusion and differentiation marker gene expression were attenuated by blockade of Erk1/2 mitogen-activated protein kinase (MAPK) pathway through pretreatment with MAPK/ Erk kinase 1 (MEK1) inhibitor PD98059, indicating that myostatin-stimulated activation of Erk1/2 negatively regulates myogenic differentiation. Activin receptor type IIb (ActRIIb) was previously suggested as the only type II membrane receptor triggering myostatin signaling. In this study, by using synthesized small interfering RNAs and dominant-negative ActRIIb, we show that myostatin failed to stimulate Erk1/2 phosphorylation and could not inhibit myoblast differentiation in ActRIIb-knockdown C2C12 cells, indicating that ActRIIb was required for myostatin-stimulated differentiation suppression. Altogether, our findings in this report provide the first evidence to reveal functional role of the Erk1/2 MAPK pathway in myostatin action as a negative regulator of muscle cell growth. (Cancer Res 2006; 66(3): 1320-6)

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“…Mst arrests muscle cells in the G 1 and G 2 phases of the cell cycle, through the up-regulation of cyclin-dependent kinase (cdk) inhibitor p21 and down-regulation of cdk-2, thereby inhibiting cell proliferation (Thomas et al, 2000). This inhibition is mediated, at least in part, through the p38 MAPK stress response pathway (Philip et al, 2005) (Figure 4). Mst also appears to directly inhibit muscle differentiation by interfering with the activity of MyoD (Langley et al, 2002).…”

Section: Fibre Number: Mediators Of Muscle Hyperplasiamentioning

confidence: 99%

Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype

Chang

2007

Animal

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The molecular basis and control of the biochemical and biophysical properties of skeletal muscle, regarded as muscle phenotype, are examined in terms of fibre number, fibre size and fibre types. A host of external factors or stimuli, such as ligand binding and contractile activity, are transduced in muscle into signalling pathways that lead to protein modifications and changes in gene expression which ultimately result in the establishment of the specified phenotype. In skeletal muscle, the key signalling cascades include the Ras-extracellular signal regulated kinase-mitogen activated protein kinase (Erk-MAPK), the phosphatidylinositol 3 0 -kinase (PI3K)-Akt1, p38 MAPK, and calcineurin pathways. The molecular effects of external factors on these pathways revealed complex interactions and functional overlap. A major challenge in the manipulation of muscle of farm animals lies in the identification of regulatory and target genes that could effect defined and desirable changes in muscle quality and quantity. To this end, recent advances in functional genomics that involve the use of micro-array technology and proteomics are increasingly breaking new ground in furthering our understanding of the molecular determinants of muscle phenotype.

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Regulation of GDF-8 signaling by the p38 MAPK

Cited by 133 publications

References 43 publications

Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

Extracellular Signal–Regulated Kinase 1/2 Mitogen-Activated Protein Kinase Pathway Is Involved in Myostatin-Regulated Differentiation Repression

Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype

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