P38α MAPK Coordinates Mitochondrial Adaptation to Caloric Surplus in Skeletal Muscle.

Excessive calorie intake leads to mitochondrial overload and triggers metabolic inflexibility and insulin resistance. In this study, we examined how attenuated p38α activity affects glucose and fat metabolism in the skeletal muscles of mice on a high-fat diet (HFD). Mice exhibiting diminished p38α activity (referred to as p38α) gained more weight and displayed elevated serum insulin levels, as well as a compromised response in the insulin tolerance test, compared to the control mice.

p38 MAPK in Glucose Metabolism of Skeletal Muscle: Beneficial or Harmful?

Skeletal muscles respond to environmental and physiological changes by varying their size, fiber type, and metabolic properties. P38 mitogen-activated protein kinase (MAPK) is one of several signaling pathways that drive the metabolic adaptation of skeletal muscle to exercise. p38 MAPK also participates in the development of pathological traits resulting from excessive caloric intake and obesity that cause metabolic syndrome and type 2 diabetes (T2D).

P38α MAPK coordinates the activities of several metabolic pathways that together induce atrophy of denervated muscles.

Physiological or pathological muscle disuse/inactivity or loss of the neural-muscular junction cause muscle atrophy. Atrophy-inducing conditions cause metabolic oxidative stress in the muscle tissue, activation of the ubiquitin-proteasome and of the autophagosome-lysosome systems, enhanced removal of the damaged proteins and organelles, and loss of muscle mass and strength. The signaling pathways that control these catabolic processes are only partially known.

Adhesion molecule Kirrel3/Neph2 is required for the elongated shape of myocytes during skeletal muscle differentiation.

Kirrel/Neph proteins are evolutionarily conserved members of the immunoglobulin superfamily of adhesion proteins. Kirrel3 is the mouse orthologue of Dumbfounded (Duf), a family member that regulates myoblast pre-fusion events in Drosophila. Yet, the role of Kirrel3 in mammalian myogenesis has not been demonstrated.

TAZ is involved in transcriptional complexes regulating smooth muscle cell differentiation.

TGFβ signaling plays an important role in the differentiation of vascular smooth muscle cells (VSMCs), yet the mechanism remains largely unknown. The study by Pagiatakis et al. identifies the transcriptional coactivator TAZ as a mediator of TGFβ signaling in VSMC-specific transcription.

Rejuvenating stem cells to restore muscle regeneration in aging.

Adult muscle stem cells, originally called satellite cells, are essential for muscle repair and regeneration throughout life. Besides a gradual loss of mass and function, muscle aging is characterized by a decline in the repair capacity, which blunts muscle recovery after injury in elderly individuals. A major effort has been dedicated in recent years to deciphering the causes of satellite cell dysfunction in aging animals, with the ultimate goal of rejuvenating old satellite cells and improving muscle function in elderly people.

Myocyte enhancer factor 2D regulates ectoderm specification and adhesion properties of animal cap cells in the early Xenopus embryo.

In Xenopus, animal cap (AC) cells give rise to ectoderm and its derivatives: epidermis and the central nervous system. Ectoderm has long been considered a default pathway of embryonic development, with cells that are not under the influence of vegetal Nodal signaling adopting an ectodermal program of gene expression. In the present study, we describe the involvement of the animally-localized maternal transcription factor myocyte enhancer factor (Mef) 2D in regulating the identity of AC cells.

Transcriptional regulation of mesoderm genes by MEF2D during early Xenopus development.

In Xenopus, specification of the three germ layers is one of the earliest developmental decisions occurring prior to gastrulation. The maternally-expressed vegetally-localized transcription factor VegT has a central role in cell autonomous specification of endoderm and in the generation of mesoderm-inducing signals. Yet, marginally-expressed transcription factors that cooperate with mesoderm-inducing signals are less investigated.

Stress-induced C/EBP homology protein (CHOP) represses MyoD transcription to delay myoblast differentiation.

When mouse myoblasts or satellite cells differentiate in culture, the expression of myogenic regulatory factor, MyoD, is downregulated in a subset of cells that do not differentiate. The mechanism involved in the repression of MyoD expression remains largely unknown. Here we report that a stress-response pathway repressing MyoD transcription is transiently activated in mouse-derived C2C12 myoblasts growing under differentiation-promoting conditions.

Studying MAP Kinase pathways during early development of Xenopus laevis.

The following chapter describes several methods involved in the detection of MAPK activities and phosphorylated proteins during early development of Xenopus laevis. The Xenopus embryo provides a powerful platform for biochemical studies. We describe here basic methods of embryo manipulations such as egg fertilization, embryo growth and maintenance, microinjection of capped RNA and antisense morpholino oligonucleotides (AMOs), and isolation of explants.

Neural ectoderm-secreted FGF initiates the expression of Nkx2.5 in cardiac progenitors via a p38 MAPK/CREB pathway.

Vertebrate heart development is derived from paired primordia of anterior dorsolateral mesoderm expressing Nkx2.5 and GATA4 transcription factors. Yet growth factors and intracellular pathways specifying heart precursor gene expression are poorly understood.

A p38 MAPK-CREB pathway functions to pattern mesoderm in Xenopus.

Dorsal-ventral patterning is specified by signaling centers secreting antagonizing morphogens that form a signaling gradient. Yet, how morphogen gradient is translated intracellularly into fate decisions remains largely unknown. Here, we report that p38 MAPK and CREB function along the dorsal-ventral axis in mesoderm patterning.

Inhibition of myoblast differentiation by tumor necrosis factor alpha is mediated by c-Jun N-terminal kinase 1 and leukemia inhibitory factor.

The proinflammatory cytokine, TNFalpha plays a major role in muscle wasting occurring in chronic diseases and muscular dystrophies. Among its other functions, TNFalpha perturbs muscle regeneration by preventing satellite cell differentiation. In the present study, the role of c-Jun N-terminal kinase (JNK), a mediator of TNFalpha, was investigated in differentiating myoblast cell lines.

Differential binding of quadruplex structures of muscle-specific genes regulatory sequences by MyoD, MRF4 and myogenin.

Four myogenic regulatory factors (MRFs); MyoD, Myf-5, MRF4 and Myogenin direct muscle tissue differentiation. Heterodimers of MRFs with E-proteins activate muscle-specific gene expression by binding to E-box motifs d(CANNTG) in their promoters or enhancers. We showed previously that in contrast to the favored binding of E-box by MyoD-E47 heterodimers, homodimeric MyoD associated preferentially with quadruplex structures of regulatory sequences of muscle-specific genes.

MyoD uses overlapping but distinct elements to bind E-box and tetraplex structures of regulatory sequences of muscle-specific genes.

Muscle differentiation and expression of muscle-specific proteins are initiated by the binding of heterodimers of the transcription factor MyoD with E2A proteins to E-box motif d(CANNTG) in promoters or enhancers of muscle-specific genes. MyoD homodimers, however, form tighter complexes with tetraplex structures of guanine-rich regulatory sequences of some muscle genes. In this work, we identified elements in MyoD that bind E-box or tetraplex structures of promoter sequences of the muscle-specific genes alpha7 integrin and sarcomeric Mitochondrial Creatine Kinase (sMtCK).

JX401, A p38alpha inhibitor containing a 4-benzylpiperidine motif, identified via a novel screening system in yeast.

In vivo screening of compounds for potential pharmacological activity is more advantageous than in vitro screening. In vivo screens eliminate the isolation of compounds that cannot cross biological membranes, are cytotoxic, or are not specific to the target. However, animal-based or even cell-based systems are usually expensive, time-consuming, and laborious.

The p38 MAPK signaling pathway: a major regulator of skeletal muscle development.

Skeletal muscle development is regulated by extracellular growth factors that transmit largely unknown signals into the cell affecting the muscle-transcription program. One intracellular signaling pathway activated during the differentiation of myogenic cell lines is p38 mitogen-activated protein kinase (MAPK). As a result of modifying the activity of p38 in myoblasts, the pathway proved essential for the expression of muscle-specific genes.

p38 MAP kinase regulates the expression of XMyf5 and affects distinct myogenic programs during Xenopus development.

The p38 MAPK signaling pathway is essential for skeletal muscle differentiation in tissue culture models. We demonstrate a novel role for p38 MAPK in myogenesis during early Xenopus laevis development. Interfering with p38 MAPK causes distinct defects in myogenesis.

Homodimeric MyoD preferentially binds tetraplex structures of regulatory sequences of muscle-specific genes.

Myogenic transcription is activated by the binding of heterodimers of the basic helix-loop-helix proteins MyoD and E12 or E47 to a consensus E-box sequence, d(CANNTG), in promoter or enhancer regions of muscle-specific genes. Homodimers of MyoD bind E-box less tightly and are less efficient activators of transcription. Recent results from our laboratory (Yafe, A.

A MyoD-generated feed-forward circuit temporally patterns gene expression during skeletal muscle differentiation.

The development and differentiation of distinct cell types is achieved through the sequential expression of subsets of genes; yet, the molecular mechanisms that temporally pattern gene expression remain largely unknown. In skeletal myogenesis, gene expression is initiated by MyoD and includes the expression of specific Mef2 isoforms and activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Here, we show that p38 activity facilitates MyoD and Mef2 binding at a subset of late-activated promoters, and the binding of Mef2D recruits Pol II.

RhoA controls myoblast survival by inducing the phosphatidylinositol 3-kinase-Akt signaling pathway.

The small GTPase RhoA regulates the expression of the myogenic transcription factor, MyoD, and the transcription of muscle-specific genes. We report that RhoA also affects the survival of differentiating myoblasts. Two signaling pathways, extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3-K)-Akt, are involved in myoblast survival.

Modification of ligand-independent B cell receptor tonic signals activates receptor editing in immature B lymphocytes.

Maturation of B lymphocytes strictly depends on the signaling competence of the B cell antigen receptor (BCR). Autoreactive receptors undergo negative selection and can be replaced by receptor editing. In addition, the process of maturation of non-self B cells and migration to the spleen, referred to as positive selection, is limited by the signaling competence of the BCR.

The mitogen-activated protein kinase cascade promotes myoblast cell survival by stabilizing the cyclin-dependent kinase inhibitor, p21WAF1 protein.

During myogenesis, proliferating myoblasts withdraw from the cell cycle and are either eliminated by programmed cell death or differentiate into mature myotubes. Previous studies indicate that mitogen-activated protein kinase (MAPK) activity is significantly induced with the onset of terminal differentiation of C2 myoblasts. We have investigated the part played by the MAPK pathway in the differentiation of C2 myoblasts.

Induction of terminal differentiation by the c-Jun dimerization protein JDP2 in C2 myoblasts and rhabdomyosarcoma cells.

Muscle cell differentiation is a result of a complex interplay between transcription factors and cell signaling proteins. Proliferating myoblasts must exit from the cell cycle prior to their differentiation. The muscle regulatory factor and myocyte enhancer factor-2 protein families play a major role in promoting muscle cell differentiation.