Skeletal muscle is comprised of heterogeneous muscle fibers that differ in their physiological and metabolic parameters. It is this diversity that enables different muscle groups to provide a variety of functional properties. In response to environmental demands, skeletal muscle remodels by activating signaling pathways to reprogram gene expression to sustain muscle performance. Studies have been performed using exercise, electrical stimulation, transgenic animal models, disease states, and microgravity to show genetic alterations and transitions of muscle fibers in response to functional demands. Various components of calcium-dependent signaling pathways and multiple transcription factors, coactivators and corepressors have been shown to be involved in skeletal muscle remodeling. Understanding the mechanisms involved in modulating skeletal muscle phenotypes can potentiate the development of new therapeutic measures to ameliorate muscular diseases.

Signaling Pathways in Skeletal Muscle Remodeling

Genomic sequencing reveals similar but limited numbers of protein-coding genes in different genomes, which begs the question of how organismal diversities are generated. Alternative pre-mRNA splicing, a widespread phenomenon in higher eukaryotic genomes, is thought to provide a mechanism to increase the complexity of the proteome and introduce additional layers for regulating gene expression in different cell types and during development. Among a large number of factors implicated in the splicing regulation are the SR protein family of splicing factors and SR protein-specific kinases. Here, we summarize the rules for SR proteins to function as splicing regulators, which depend on where they bind in exons versus intronic regions, on alternative exons versus flanking competing exons, and on cooperative as well as competitive binding between different SR protein family members on many of those locations. We review the importance of cycles of SR protein phosphorylation/dephosphorylation in the splicing reaction with emphasis on the recent molecular insight into the role of SR protein phosphorylation in early steps of spliceosome assembly. Finally, we highlight recent discoveries of SR protein-specific kinases in transducing growth signals to regulate alternative splicing in the nucleus and the connection of both SR proteins and SR protein kinases to human diseases, particularly cancer.

/pdf/regulation-of-splicing-by-sr-proteins-and-sr-protein-1tg61mfl35.pdf

Regulation of Splicing by SR proteins and SR Protein-Specific Kinases

MEF2C transcription factor controls chondrocyte hypertrophy and bone development

Transfer learning enables predictions in network biology

The zinc-finger transcription factors GATA4 and GATA6 play critical roles in embryonic development. Mouse embryos lacking GATA4 die at embryonic day (E) 8.5 because of failure of ventral foregut closure and cardiac bifida, whereas GATA6 is essential for development of the visceral endoderm. Although mice that are heterozygous for either a GATA4 or GATA6 null allele are normal, we show that compound heterozygosity of GATA4 and GATA6 results in embryonic lethality by E13.5 accompanied by a spectrum of cardiovascular defects, including thin-walled myocardium, ventricular and aortopulmonary septal defects, and abnormal smooth muscle development. Myocardial hypoplasia in GATA4/GATA6 double heterozygous mutant embryos is associated with reduced proliferation of cardiomyocytes, diminished expression of the myogenic transcription factor MEF2C (myocyte enhancer factor 2C), and down-regulation of β-myosin heavy chain expression, a key determinant of cardiac contractility. These findings reveal a threshold of GATA4 and GATA6 activity that is required for gene expression in the developing cardiovascular system and underscore the potential of recessive mutations to perturb the delicate regulation of cardiovascular development.

https://www.pnas.org/content/pnas/103/30/11189.full.pdf

A threshold of GATA4 and GATA6 expression is required for cardiovascular development

Myocyte enhancer factor 2 (MEF2) plays essential roles in transcriptional control of muscle development. However, signaling pathways acting downstream of MEF2 are largely unknown. Here, we performed a microarray analysis using Mef2c-null mouse embryos and identified a novel MEF2-regulated gene encoding a muscle-specific protein kinase, Srpk3, belonging to the serine arginine protein kinase (SRPK) family, which phosphorylates serine/arginine repeat-containing proteins. The Srpk3 gene is specifically expressed in the heart and skeletal muscle from embryogenesis to adulthood and is controlled by a muscle-specific enhancer directly regulated by MEF2. Srpk3-null mice display a new entity of type 2 fiber-specific myopathy with a marked increase in centrally placed nuclei; while transgenic mice overexpressing Srpk3 in skeletal muscle show severe myofiber degeneration and early lethality. We conclude that normal muscle growth and homeostasis require MEF2-dependent signaling by Srpk3.

/pdf/centronuclear-myopathy-in-mice-lacking-a-novel-muscle-24yrw3sh9n.pdf

Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2

The increase of combination number according to the increase of variables is a serious problem in using section optimization for steel structures. Response Surface Method (RSM) which uses approximate functions made by sampling data was proofed as one of effective optimization methods. This paper shows features of the proposed method that combined with genetic algorithm by applying it to allowable stress design of a middle rise steel structure and changing the setting of RSM which are a response surface algorithm and a space filler algorithm. In addition, the feature of the optimized structures is analyzed by nonlinear dynamic response analysis. 

/pdf/section-optimization-of-rigid-steel-frames-using-response-1f1fzof3.pdf

Section optimization of rigid steel frames using response surface models

Seismic design for super high-rise building with dampers using multiple step optimization

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Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2

Section optimization of rigid steel frames using response surface models

Seismic design for super high-rise building with dampers using multiple step optimization