Age-related reductions in expression of serum response factor and myocardin-related transcription factor A in mouse skeletal muscles

Sakuma, Kunihiro; Akiho, Mai; Nakashima, Hiroyuki; Akima, Hiroshi; Yasuhara, Masahiro

doi:10.1016/j.bbadis.2008.03.008

Cited by 53 publications

(68 citation statements)

References 40 publications

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“…Since SRF activities are known to deteriorate in some aging cells (53), it will be of great interest to explore potential contributions of age-dependent SRF activity changes in the aging retinal endothelium of human AMD patients. Furthermore, our work might suggest modulation of EC SRF activity, as well as elevation of thrombospondin activity, as therapeutic options for the treatment of some NV AMD pathologies, such as RAP and MacTel.…”

Section: Discussionmentioning

confidence: 99%

Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae

Weinl¹,

Riehle²,

Park³

et al. 2013

J. Clin. Invest.

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Retinal vessel homeostasis ensures normal ocular functions. Consequently, retinal hypovascularization and neovascularization, causing a lack and an excess of vessels, respectively, are hallmarks of human retinal pathology. We provide evidence that EC-specific genetic ablation of either the transcription factor SRF or its cofactors MRTF-A and MRTF-B, but not the SRF cofactors ELK1 or ELK4, cause retinal hypovascularization in the postnatal mouse eye. Inducible, EC-specific deficiency of SRF or MRTF-A/MRTF-B during postnatal angiogenesis impaired endothelial tip cell filopodia protrusion, resulting in incomplete formation of the retinal primary vascular plexus, absence of the deep plexi, and persistence of hyaloid vessels. All of these features are typical of human hypovascularization-related vitreoretinopathies, such as familial exudative vitreoretinopathies including Norrie disease. In contrast, conditional EC deletion of Srf in adult murine vessels elicited intraretinal neovascularization that was reminiscent of the age-related human pathologies retinal angiomatous proliferation and macular telangiectasia. These results indicate that angiogenic homeostasis is ensured by differential stage-specific functions of SRF target gene products in the developing versus the mature retinal vasculature and suggest that the actin-directed MRTF-SRF signaling axis could serve as a therapeutic target in the treatment of human vascular retinal diseases.

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Section: Discussionmentioning

confidence: 99%

Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae

Weinl¹,

Riehle²,

Park³

et al. 2013

J. Clin. Invest.

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“…64 Mice also show decreasing levels of SRF with advancing age. 65 One of the cofactors for SRF activity, MRTF-A, was also reduced in aged skeletal muscle. 65 Interestingly, transgenic mice overexpressing a dominant-negative form of MRTF-A show skeletal muscle atrophy.…”

Section: Blood Vesselsmentioning

confidence: 99%

“…65 One of the cofactors for SRF activity, MRTF-A, was also reduced in aged skeletal muscle. 65 Interestingly, transgenic mice overexpressing a dominant-negative form of MRTF-A show skeletal muscle atrophy. 61 Finally, skeletal muscle from a spontaneous mouse mutant (merosin, dy mice), which is a model for muscular dystrophy, showed attenuated SRF expression.…”

Section: Blood Vesselsmentioning

confidence: 99%

Role of serum response factor in the pathogenesis of disease

Miano

2010

Laboratory Investigation

123

100

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Serum response factor (SRF) is a ubiquitously expressed transcription factor that binds to a DNA cis element known as the CArG box, which is found in the proximal regulatory regions of over 200 experimentally validated target genes. Genetic deletion of SRF is incompatible with life in a variety of animals from different phyla. In mice, loss of SRF throughout the early embryo results in gastrulation defects precluding analyses in individual organ systems. Genetic inactivation studies using conditional or inducible promoters directing the expression of the bacteriophage Cre recombinase have shown a vital role for SRF in such cellular processes as contractility, cell migration, synaptic activity, inflammation, and cell survival. A growing number of experimental and human diseases are associated with changes in SRF expression, suggesting that SRF has a role in the pathogenesis of disease. This review summarizes data from experimental model systems and human pathology where SRF expression is either deliberately or naturally altered. Genomic DNA is a quaternary code comprising proteincoding and non-protein-coding sequences. While the protein-coding sequences are well-defined and increasingly understood, we are only beginning to elucidate the hidden information within the vast landscape of the non-proteincoding sequences. The field of comparative genomics has facilitated the identification of transcription factor-binding sites (TFBS) and microRNAs (miRs), which, aside from repetitive DNA sequences, are among the more easily decipherable non-protein-coding sequences in the human genome. Together, TFBS and miRs have essential roles in cell fate determination and cellular homeostasis of most life forms. Sequence variations (eg, single-nucleotide polymorphisms, SNPs) in the TFBS, miRs, and miR target sequences alter gene/protein expression and thus disturb homeostasis leading to disease. 1-4 A major imperative, therefore, is decoding the non-protein-coding genome relating to gene regulation to gain a full understanding of how DNA-binding transcription factors and the estimated one million or more TFBS direct normal biological processes.Serum response factor (SRF) is the founding member of the MADS-box family of transcription factors 5 and is one of the best understood DNA-binding proteins in the human proteome. The DNA-binding properties of SRF and its molecular cloning were first defined in the laboratory of Richard Treisman. 6,7 SRF has relatively low intrinsic transcriptional activity, but its interaction with over 60 cofactors confers strong transactivation potential in a cell-and context-specific manner. At least two major signaling pathways converge upon SRF to direct the programs of gene expression. 8,9 The classic pathway involves growth factor stimulation and mitogen-activated protein kinase signaling leading to the phosphorylation of the SRF cofactor, ELK1, and the activation of growth-related genes. 10,11 The second regulatory pathway occurs through Rho-dependent changes in actin dynamics. 12 In this pathway, si...

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“…A key marker for SkM is MyoD, and SRF, which belongs to the MCM1-agamous-ARG80-deficiens-SRF (MADS)-box family of transcription factors, is known to directly regulate MyoD expression [48,49]. Very recent studies have suggested that the expression of this important SkM transcription factor is decreased in aged SkM [50,51]. We therefore assessed the role of SRF in the discrepant SkM differentiation capacity of hDE-MSCs versus adult BMMSCs.…”

Section: Expression Levels Of Srf Affect the Ability Of Differentiatimentioning

confidence: 99%

Age-Related Decreases of Serum-Response Factor Levels in Human Mesenchymal Stem Cells Are Involved in Skeletal Muscle Differentiation and Engraftment Capacity

Ting

Yen

2014

Stem Cells and Development

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Skeletal muscle (SkM) comprise *40% of human body weight. Injury or damage to this important tissue can result in physical disability, and in severe cases is difficult for its endogenous stem cell-the satellite cellto reverse effectively. Mesenchymal stem cells (MSC) are postnatal progenitor/stem cells that possess multilineage mesodermal differentiation capacity, including toward SkM. Adult bone marrow (BM) is the beststudied source of MSCs; however, aging also decreases BMMSC numbers and can adversely affect differentiation capacity. Therefore, we asked whether human sources of developmentally early stage mesenchymal stem cells (hDE-MSCs) isolated from embryonic stem cells, fetal bone, and term placenta could be cellular sources for SkM repair. Under standard muscle-inducing conditions, hDE-MPCs differentiate toward a SkM lineage rather than cardiomyocytic or smooth muscle lineages, as evidenced by increased expression of SkM-associated markers and in vitro myotube formation. In vivo transplantation revealed that SkM-differentiated hDE-MSCs can efficiently incorporate into host SkM tissue in a mouse model of SkM injury. In contrast, adult BMMSCs do not express SkM-associated genes after in vitro SkM differentiation nor engraft in vivo. Further investigation of possible factors responsible for this difference in SkM differentiation potential revealed that, compared with adult BMMSCs, hDE-MSCs expressed higher levels of serum response factor (SRF), a transcription factor critical for SkM lineage commitment. Moreover, knockdown of SRF in hDE-MSCs resulted in decreased expression of SkM-related genes after in vitro differentiation and decreased in vivo engraftment. Our results implicate SRF as a key factor in age-related SkM differentiation capacity of MSCs, and demonstrate that hDEMSCs are possible candidates for SkM repair.

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Age-related reductions in expression of serum response factor and myocardin-related transcription factor A in mouse skeletal muscles

Cited by 53 publications

References 40 publications

Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae

Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae

Role of serum response factor in the pathogenesis of disease

Age-Related Decreases of Serum-Response Factor Levels in Human Mesenchymal Stem Cells Are Involved in Skeletal Muscle Differentiation and Engraftment Capacity

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