Pctaire1/Cdk16 promotes skeletal myogenesis by inducing myoblast migration and fusion

The Cdk-related protein kinase Pctaire1/Cdk16 is abundantly expressed in brain, testis and skeletal muscle. Functional roles of Pctaire1 such as regulation of neuron migration and neurite outgrowth thus far have been mainly elucidated in the field of nervous system development. Although these regulations based on cytoskeletal rearrangements evoke a possible role of Pctaire1 in the development of skeletal muscle, little is known in this regard. In this study, we demonstrated that myogenic differentiation and subsequent fusion is promoted in Pctaire1 overexpressing cells, and conversely, is inhibited in the knockdown cells. Furthermore, our findings suggest that Pctaire1 exerts promyogenic effects by regulating myoblast migration and process formation during skeletal myogenesis.     

Dystrophins and DAPs are expressed in adipose tissue and are regulated by adipogenesis and extracellular matrix

The dystrophin-associated protein complex (DAPC), consisting of dystrophin, dystroglycans, sarcoglycans, dystrobrevins and syntrophins, provides a linkage between the cytoskeleton and the extracellular matrix. The disruption of DAPC leads to Duchenne/Becker muscular dystrophy and other neuromuscular diseases. Although adipose-derived stem cells had been used for the experimental treatment of Duchenne/Becker disease with promising results, little is known on the expression and function of DAPC in adipose tissue. Here we show that visceral and subcutaneous rat adipose depots express mRNAs for all known dystrophin isoforms, utrophin, α- and β-dystrobrevins, and α-, βI-, βII-, and γII-syntrophins. Visceral and subcutaneous rat preadipocytes express Dp116 and Dp71 mRNAs and proteins, and this expression is differentially regulated during adipogenesis. Rat preadipocytes also express β-dystrobrevin, α-, βI-, βII- and γII-syntrophins, β-dystroglycan and β-, δ-, and ε-sarcoglycans with no changes during adipogenesis. We also show that α-dystrobrevin increases their expression during adipose differentiation and extracellular matrix differentially regulates the expression of dystrophin isoforms mRNAs during adipogenesis. Our results show that DAPC components are expressed in adipose tissues and suggest that this complex has a role on the adipose biology.     

Community effect triggers terminal differentiation of myogenic cells derived from muscle satellite cells by quenching Smad signaling

A high concentration of bone morphogenetic proteins (BMPs) stimulates myogenic progenitor cells to undergo heterotopic osteogenic differentiation. However, the physiological role of the Smad signaling pathway during terminal muscle differentiation has not been resolved. We report here that Smad1/5/8 was phosphorylated and activated in undifferentiated growing mouse myogenic progenitor Ric10 cells without exposure to any exogenous BMPs. The amount of phosphorylated Smad1/5/8 was severely reduced during precocious myogenic differentiation under the high cell density culture condition even in growth medium supplemented with a high concentration of serum. Inhibition of the Smad signaling pathway by dorsomorphin, an inhibitor of Smad activation, or noggin, a specific antagonist of BMP, induced precocious terminal differentiation of myogenic progenitor cells in a cell density-dependent fashion even in growth medium. In addition, Smad1/5/8 was transiently activated in proliferating myogenic progenitor cells during muscle regeneration in rats. The present results indicate that the Smad signaling pathway is involved in a critical switch between growth and differentiation of myogenic progenitor cells both in vitro and in vivo. Furthermore, precocious cell density-dependent myogenic differentiation suggests that a community effect triggers the terminal muscle differentiation of myogenic cells by quenching the Smad signaling.     

IGF-I and vitamin C promote myogenic differentiation of mouse and human skeletal muscle cells at low temperatures

In a previous study investigating the effects of low temperature on skeletal muscle differentiation, we demonstrated that C2C12 mouse myoblasts cultured at 30 °C do not express myogenin, a myogenic regulatory factor (MRF), or fuse into multinucleated myotubes. At this low temperature, the myoblasts continuously express Id3, a negative regulator of MRFs, and do not upregulate muscle-specific microRNAs. In this study, we examined if insulin-like growth factor-I (IGF-I) and a stable form of vitamin C (L-ascorbic acid phosphate) could alleviate the low temperature-induced inhibition of myogenic differentiation in C2C12 cells. Although the addition of either IGF-I or vitamin C alone could promote myogenin expression in C2C12 cells at 30 °C, elongated multinucleated myotubes were not formed unless both IGF-I and vitamin C were continuously administered. In human skeletal muscle cells, low temperature-induced blockage of myogenic differentiation was also ameliorated by exogenous IGF-I and vitamin C. In addition, we demonstrated that satellite cells of IGF-I overexpressing transgenic mice in single-fiber culture expressed myogenin at a higher level than those of wild-type mice at 30 °C. This study suggests that body temperature plays an important role in myogenic differentiation of endotherms, but the sensitivity to low temperature could be buffered by certain factors in vivo, such as IGF-I and vitamin C.     

A protein-kinase, IFN-inducible double-stranded RNA dependent inhibitor and repressor of p58 (PRKRIR) enhances type I IFN-mediated antiviral response through the stability control of RIG-I protein

The cellular RIG-I-like receptor (RLR) senses pathogenic RNA molecular patterns and transmits signals for type I interferon (IFN) production. It acts as a center for antiviral responses, and large numbers of RIG-I (retinoic acid inducible gene-I) interacting proteins are identified as signaling regulators. In the present study, we report PRKRIR, a negative regulator of PKR inhibitor, as a novel RIG-I interacting protein. In HEK293FT cells, PRKRIR synergistically enhances type I IFN production mediated by a signal activated- or constitutively active form of RIG-I. The C-terminal domain of the PRKRIR was required for physical interaction and the signal augmentation. The PRKRIR blocks poly-ubiquitination and protein degradation of RIG-I, thereby increasing cellular levels of RIG-I proteins. Furthermore, overexpression of PRKRIR, along with a signal activated- or constitutively active form of RIG-I, efficiently inhibits virus replication in the infected host. In conclusion, PRKRIR provides a novel positive regulator controlling the RIG-I-IFN production system through protein stability control.     

14-3-3 proteins in neurodegeneration

Among the first reported functions of 14-3-3 proteins was the regulation of tyrosine hydroxylase (TH) activity suggesting a possible involvement of 14-3-3 proteins in Parkinson's disease. Since then the relevance of 14-3-3 proteins in the pathogenesis of chronic as well as acute neurodegenerative diseases, including Alzheimer's disease, polyglutamine diseases, amyotrophic lateral sclerosis and stroke has been recognized. The reported function of 14-3-3 proteins in this context are as diverse as the mechanism involved in neurodegeneration, reaching from basal cellular processes like apoptosis, over involvement in features common to many neurodegenerative diseases, like protein stabilization and aggregation, to very specific processes responsible for the selective vulnerability of cellular populations in single neurodegenerative diseases.Here, we review what is currently known of the function of 14-3-3 proteins in nervous tissue focussing on the properties of 14-3-3 proteins important in neurodegenerative disease pathogenesis.