CREB Is Activated by Muscle Injury and Promotes Muscle Regeneration

Stewart, Randi; Flechner, Lawrence; Montminy, Marc; Berdeaux, Rebecca

doi:10.1371/journal.pone.0024714

Cited by 66 publications

(79 citation statements)

References 48 publications

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“…SIK1 is rapidly degraded in undifferentiated myoblasts, but Sik1 mRNA and SIK1 protein accumulate during differentiation of primary muscle progenitors ex vivo, consistent with enrichment of Sik1 transcripts in differentiating regions of the somites in mouse embryos (34). We hypothesize that the observed accumulation of cAMP before muscle cell fusion exerts a priming effect (4) in part by stimulating CREB-dependent transcription of Sik1 mRNA (14,39) and by stabilization of SIK1 protein by the mechanism we elucidated. Temporal control of SIK1 expression may affect differentiation, because SIK1 stability increases during myogenesis.…”

Section: Discussionsupporting

confidence: 62%

“…Degradation could maintain low SIK1 levels and prevent aberrant differentiation of muscle progenitor cells. In response to muscle injury, muscle progenitors become activated and undergo myogenesis with concomitant increases in intramuscular cAMP (40), CREB activity, and Sik1 mRNA (39). SIK1 also exerts protective effects on degenerating mouse myofibers expressing dominant-negative CREB (14).…”

Section: Discussionmentioning

confidence: 99%

“…C2C12 and HEK293T cells (ATCC) were cultured in DMEM and 10% (vol/vol) FBS. Primary mouse myoblasts were isolated from neonatal ICR mice with approval by the University of Texas at Houston institutional animal care and use committee (AWC-08-125, -11-096, and -11-094) and purified by density-gradient centrifugation (39). High-density myoblasts were induced to differentiate by incubation for up to 5 d in differentiation medium [DM: DMEM and 2% (vol/vol) horse serum], when most cells have fused into myotubes.…”

Section: Methodsmentioning

confidence: 99%

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Regulation of SIK1 abundance and stability is critical for myogenesis

Stewart¹,

Akhmedov²,

Robb³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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cAMP signaling can both promote and inhibit myogenic differentiation, but little is known about the mechanisms mediating promyogenic effects of cAMP. We previously demonstrated that the cAMP response element-binding protein (CREB) transcriptional target salt-inducible kinase 1 (SIK1) promotes MEF2 activity in myocytes via phosphorylation of class II histone deacetylase proteins (HDACs). However, it was unknown whether SIK1 couples cAMP signaling to the HDAC-MEF2 pathway during myogenesis and how this response could specifically occur in differentiating muscle cells. To address these questions, we explored SIK1 regulation and function in muscle precursor cells before and during myogenic differentiation. We found that in primary myogenic progenitor cells exposed to cAMP-inducing agents, Sik1 transcription is induced, but the protein is rapidly degraded by the proteasome. By contrast, sustained cAMP signaling extends the half-life of SIK1 in part by phosphorylation of Thr475, a previously uncharacterized site that we show can be phosphorylated by PKA in cell-free assays. We also identified a functional PEST domain near Thr475 that contributes to SIK1 degradation. During differentiation of primary myogenic progenitor cells, when PKA activity has been shown to increase, we observe elevated Sik1 transcripts as well as marked accumulation and stabilization of SIK1 protein. Depletion of Sik1 in primary muscle precursor cells profoundly impairs MEF2 protein accumulation and myogenic differentiation. Our findings support an emerging model in which SIK1 integrates cAMP signaling with the myogenic program to support appropriate timing of differentiation. M yoblast differentiation is driven by a transcriptional cascade that is subject to precise temporal control during development as well as after acute muscle injury (1). The second messenger cAMP and its primary effector PKA are known to contribute to myoblast proliferation in the developing dermomyotome (2), to promote migration and fusion of muscle precursor cells (3, 4), and to exert potent anabolic effects on adult skeletal muscle (5). During differentiation of myoblasts ex vivo, intracellular cAMP peaks transiently before cell-cell fusion (6, 7), and PKA signaling is required for expression of differentiation markers in cultured myoblasts (8) and in mouse embryos (2). However, sustained cAMP-PKA signaling prevents myogenic differentiation, in part through inhibition of basic helix-loop-helix and MADS transcription factors (9-11). The mechanisms by which a transient peak of cAMP promotes myoblast differentiation are still poorly understood. Because ligands that induce cAMP production promote muscle regeneration (5), it is important to identify promyogenic cAMP signaling effectors.The transcription factor CREB (cAMP response elementbinding protein) is a key effector of cAMP-PKA in many cell types (12). CREB phosphorylation is induced during early stages of vertebrate myogenesis (2, 13), and CREB activity is required in mice for dermomyotome development (2). We previously...

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Regulation of SIK1 abundance and stability is critical for myogenesis

Stewart¹,

Akhmedov²,

Robb³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…cAMP binding to PKA regulatory subunits permits release of catalytic subunits that phosphorylate numerous target proteins, including metabolic enzymes, structural proteins, ion channels, and transcription factors such as CREBs. PKA, through CREB, controls myogenesis induced by Wnt proteins during mouse embryo development (Chen et al, 2005) and promotes muscle regeneration in vivo after acute muscle injury (Stewart et al, 2011). cAMP-PKA signalling is spatially restricted by AKAPs in skeletal myofibres (Dessauer, 2009).…”

Section: Synemin Modulates the Hypertrophic Response Following Mechanmentioning

confidence: 99%

“…The reason for this difference is not yet clear and warrants further characterisation. Based on the involvement of PKA signalling in myogenesis (Stewart et al, 2011), synemin might influence satellite cell behaviour through its role in the regulation of PKA activity.…”

Section: Synemin Affects Behaviour Of Satellite Cells During Mechanicmentioning

confidence: 99%

Synemin acts as a regulator of signalling molecules in skeletal muscle hypertrophy

Li¹,

Parlakian²,

Coletti³

et al. 2014

Journal of Cell Science

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Synemin, a type IV intermediate filament (IF) protein, forms a bridge between IFs and cellular membranes. As an A-kinase-anchoring protein, it also provides temporal and spatial targeting of protein kinase A (PKA). However, little is known about its functional roles in either process. To better understand its functions in muscle tissue, we generated synemin-deficient (Synm 2/2 ) mice. Synm 2/2 mice displayed normal development and fertility but showed a mild degeneration and regeneration phenotype in myofibres and defects in sarcolemma membranes. Following mechanical overload, Synm 2/2 mice muscles showed a higher hypertrophic capacity with increased maximal force and fatigue resistance compared with control mice. At the molecular level, increased remodelling capacity was accompanied by decreased myostatin (also known as GDF8) and atrogin (also known as FBXO32) expression, and increased follistatin expression. Furthermore, the activity of muscle-mass control molecules (the PKA RIIa subunit, p70S6K and CREB1) was increased in mutant mice. Finally, analysis of muscle satellite cell behaviour suggested that the absence of synemin could affect the balance between self-renewal and differentiation of these cells. Taken together, our results show that synemin is necessary to maintain membrane integrity and regulates signalling molecules during muscle hypertrophy.

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Activity‐Dependent Induction of Younger Biological Phenotypes

Lissek

2022

Advanced Biology

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In several mammalian species, including humans, complex stimulation patterns such as cognitive and physical exercise lead to improvements in organ function, organism health and performance, as well as possibly longer lifespans. A framework is introduced here in which activity‐dependent transcriptional programs, induced by these environmental stimuli, move somatic cells such as neurons and muscle cells toward a state that resembles younger cells to allow remodeling and adaptation of the organism. This cellular adaptation program targets several process classes that are heavily implicated in aging, such as mitochondrial metabolism, cell–cell communication, and epigenetic information processing, and leads to functional improvements in these areas. The activity‐dependent gene program (ADGP) can be seen as a natural, endogenous cellular reprogramming mechanism that provides deep insight into the principles of inducible improvements in cell and organism function and can guide the development of therapeutic approaches for longevity. Here, these ADGPs are analyzed, exemplary critical molecular nexus points such as cAMP response element‐binding protein, myocyte enhancer factor 2, serum response factor, and c‐Fos are identified, and it is explored how one may leverage them to prevent, attenuate, and reverse human aging‐related decline of body function.

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CREB Is Activated by Muscle Injury and Promotes Muscle Regeneration

Cited by 66 publications

References 48 publications

Regulation of SIK1 abundance and stability is critical for myogenesis

Regulation of SIK1 abundance and stability is critical for myogenesis

Synemin acts as a regulator of signalling molecules in skeletal muscle hypertrophy

Activity‐Dependent Induction of Younger Biological Phenotypes

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