http://www.skeletalmusclejournal.com The most accessed research articles published by Skeletal Muscle 2012-05-07T00:00:00Z Background: Mice lacking MyoD exhibit delayed skeletal muscle regeneration and markedly enhanced numbers of satellite cells. Myoblasts isolated from MyoD-/- myoblasts proliferate more rapidly than wild type myoblasts, display a dramatic delay in differentiation, and continue to incorporate BrdU after serum withdrawal. Methods: Primary myoblasts isolated from wild type and MyoD-/- mutant mice were examined by microarray analysis and further characterized by cell and molecular experiments in cell culture. Results: We found that NF-kappaB, a key regulator of cell-cycle withdrawal and differentiation, aberrantly maintains nuclear localization and transcriptional activity in MyoD-/- myoblasts. As a result, expression of cyclin D is maintained during serum withdrawal, inhibiting expression of muscle-specific genes and progression through the differentiation program. Sustained nuclear localization of cyclin E, and a concomitant increase in cdk2 activity maintains S-phase entry in MyoD-/- myoblasts even in the absence of mitogens. Importantly, this deficit was rescued by forced expression of IkappaBalphaSR, a non-degradable mutant of IkappaBalpha, indicating that inhibition of NF-kappaB is sufficient to induce terminal myogenic differentiation in the absence of MyoD. Conclusion: MyoD-induced cytoplasmic relocalization of NF-kappaB is an essential step in linking cell-cycle withdrawal to the terminal differentiation of skeletal myoblasts. These results provide important insight into the unique functions of MyoD in regulating the switch from progenitor proliferation to terminal differentiation. http://www.skeletalmusclejournal.com/content/2/1/6 Maura Parker Julia von Maltzahn Nadine Bakkar Ban Al-Joubori Jeff Ishibashi Denis Guttridge Michael Rudnicki Skeletal Muscle 2012, null:6 2012-04-27T00:00:00Z doi:10.1186/2044-5040-2-6 /content/figures/2044-5040-2-6-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 6 2012-04-27T00:00:00Z PDF A highly conserved signaling pathway involving insulin-like growth factor 1 (IGF1), and a cascade of intracellular components that mediate its effects, plays a major role in the regulation of skeletal muscle growth. A central component in this cascade is the kinase Akt, also called protein kinase B (PKB), which controls both protein synthesis, via the kinases mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3β (GSK3β), and protein degradation, via the transcription factors of the FoxO family. In this paper, we review the composition and function of this pathway in skeletal muscle fibers, focusing on evidence obtained in vivo by transgenic and knockout models and by muscle transient transfection experiments. Although this pathway is essential for muscle growth during development and regeneration, its role in adult muscle response to mechanical load is less clear. A full understanding of the operation of this pathway could help to design molecularly targeted therapeutics aimed at preventing muscle wasting, which occurs in a variety of pathologic contexts and in the course of aging. http://www.skeletalmusclejournal.com/content/1/1/4 Stefano Schiaffino Cristina Mammucari Skeletal Muscle 2011, null:4 2011-01-24T00:00:00Z doi:10.1186/2044-5040-1-4 /content/figures/2044-5040-1-4-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 4 2011-01-24T00:00:00Z XML Background: The use of the Cre/loxP system for gene targeting has been proven to be a powerful tool for understanding gene function. The purpose of this study was to create and characterize an inducible, skeletal muscle-specific Cre transgenic mouse strain. Methods: To achieve skeletal muscle-specific expression, the human alpha-skeletal actin promoter was used to drive expression of a chimeric Cre recombinase containing two mutated estrogen receptor ligand-binding domains. Results: Western blot analysis, PCR and beta-galactosidase staining confirmed that Cre-mediated recombination was restricted to limb and craniofacial skeletal muscles only after tamoxifen administration. Conclusions: A transgenic mouse was created that allows inducible, gene targeting of floxed genes in adult skeletal muscle of different developmental origins. This new mouse will be of great utility to the skeletal muscle community. http://www.skeletalmusclejournal.com/content/2/1/8 John McCarthy Ratchakrit Srikuea Tyler Kirby Charlotte Peterson Karyn Esser Skeletal Muscle 2012, null:8 2012-05-07T00:00:00Z doi:10.1186/2044-5040-2-8 /content/figures/2044-5040-2-8-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 8 2012-05-07T00:00:00Z PDF The repair process of damaged tissue involves the coordinated activities of several cell types in response to local and systemic signals. Following acute tissue injury, infiltrating inflammatory cells and resident stem cells orchestrate their activities to restore tissue homeostasis. However, during chronic tissue damage, such as in muscular dystrophies, the inflammatory-cell infiltration and fibroblast activation persists, while the reparative capacity of stem cells (satellite cells) is attenuated. Abnormal dystrophic muscle repair and its end stage, fibrosis, represent the final common pathway of virtually all chronic neurodegenerative muscular diseases. As our understanding of the pathogenesis of muscle fibrosis has progressed, it has become evident that the muscle provides a useful model for the regulation of tissue repair by the local microenvironment, showing interplay among muscle-specific stem cells, inflammatory cells, fibroblasts and extracellular matrix components of the mammalian wound-healing response. This article reviews the emerging findings of the mechanisms that underlie normal versus aberrant muscle-tissue repair. http://www.skeletalmusclejournal.com/content/1/1/21 Christopher Mann Eusebio Perdiguero Yacine Kharraz Susana Aguilar Patrizia Pessina Antonio Serrano Pura Munoz-Canoves Skeletal Muscle 2011, null:21 2011-05-04T00:00:00Z doi:10.1186/2044-5040-1-21 /content/figures/2044-5040-1-21-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 21 2011-05-04T00:00:00Z XML Background: Similar to replicating myoblasts, many rhabdomyosarcoma cells express the myogenic determination gene MyoD. In contrast to myoblasts, rhabdomyosarcoma cells do not make the transition from a regulative growth phase to terminal differentiation. Previously we demonstrated that the forced expression of MyoD with its E-protein dimerization partner was sufficient to induce differentiation and suppress multiple growth-promoting genes, suggesting that the dimer was targeting a switch that regulated the transition from growth to differentiation. Our data also suggested that a balance between various inhibitory transcription factors and MyoD activity kept rhabdomyosarcomas trapped in a proliferative state. Methods: Potential myogenic co-factors were tested for their ability to drive differentiation in rhabdomyosarcoma cell culture models, and their relation to MyoD activity determined through molecular biological experiments. Results: Modulation of the transcription factors RUNX1 and ZNF238 can induce differentiation in rhabdomyosarcoma cells and their activity is integrated, at least in part, through the activation of miR-206, which acts as a genetic switch to transition the cell from a proliferative growth phase to differentiation. The inhibitory transcription factor MSC also plays a role in controlling miR-206, appearing to function by occluding a binding site for MyoD in the miR-206 promoter. Conclusions: These findings support a network model composed of coupled regulatory circuits with miR-206 functioning as a switch regulating the transition from one stable state (growth) to another (differentiation). http://www.skeletalmusclejournal.com/content/2/1/7 Kyle MacQuarrie Zizhen Yao Janet Young Yi Cao Stephen Tapscott Skeletal Muscle 2012, null:7 2012-04-29T00:00:00Z doi:10.1186/2044-5040-2-7 /content/figures/2044-5040-2-7-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 7 2012-04-29T00:00:00Z PDF In skeletal muscle, the excitation-contraction (EC) coupling machinery mediates the translation of the action potential transmitted by the nerve into intracellular calcium release and muscle contraction. EC coupling requires a highly specialized membranous structure, the triad, composed of a central T-tubule surrounded by two terminal cisternae from the sarcoplasmic reticulum. While several proteins located on these structures have been identified, mechanisms governing T-tubule biogenesis and triad formation remain largely unknown. Here, we provide a description of triad structure and plasticity and review the role of proteins that have been linked to T-tubule biogenesis and triad formation and/or maintenance specifically in skeletal muscle: caveolin 3, amphiphysin 2, dysferlin, mitsugumins, junctophilins, myotubularin, ryanodine receptor, and dihydhropyridine Receptor. The importance of these proteins in triad biogenesis and subsequently in muscle contraction is sustained by studies on animal models and by the direct implication of most of these proteins in human myopathies. http://www.skeletalmusclejournal.com/content/1/1/26 Lama Al-Qusairi Jocelyn Laporte Skeletal Muscle 2011, null:26 2011-07-13T00:00:00Z doi:10.1186/2044-5040-1-26 /content/figures/2044-5040-1-26-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 26 2011-07-13T00:00:00Z XML Background: The p38α mitogen-activated protein kinase (MAPK) is a critical mediator of myoblast differentiation, and does so in part through the phosphorylation and regulation of several transcription factors and chromatin remodelling proteins. However, whether p38α is involved in processes other than gene regulation during myogenesis is currently unknown, and why other p38 isoforms cannot compensate for its loss is unclear. Methods: To further characterise the involvement of p38α during myoblast differentiation, we developed and applied a simple technique for identifying relevant in vivo kinase substrates and their phosphorylation sites. In addition to identifying substrates for one kinase, the technique can be used in vitro to compare multiple kinases in the same experiment, and we made use of this to study the substrate specificities of the p38α and β isoforms. Results: Applying the technique to p38α resulted in the identification of seven in vivo phosphorylation sites on six proteins, four of which are cytoplasmic, in lysate derived from differentiating myoblasts. An in vitro comparison with p38β revealed that substrate specificity does not discriminate these two isoforms, but rather that their distinguishing characteristic appears to be cellular localisation. Conclusion: Our results suggest p38α has a novel cytoplasmic role during myogenesis and that its unique cellular localisation may be why p38β and other isoforms cannot compensate for its absence. The substrate-finding approach presented here also provides a necessary tool for studying the hundreds of protein kinases that exist and for uncovering the deeper mechanisms of phosphorylation-dependent cell signalling. http://www.skeletalmusclejournal.com/content/2/1/5 James Knight Ruijun Tian Robin Lee Fangjun Wang Ariane Beauvais Hanfa Zou Lynn Megeney Anne-Claude Gingras Tony Pawson Daniel Figeys Rashmi Kothary Skeletal Muscle 2012, null:5 2012-03-06T00:00:00Z doi:10.1186/2044-5040-2-5 /content/figures/2044-5040-2-5-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 5 2012-03-06T00:00:00Z XML The transforming growth factor-beta (TGF-β) superfamily consists of a variety of cytokines expressed in many different cell types including skeletal muscle. Members of this superfamily that are of particular importance in skeletal muscle are TGF-β1, mitogen-activated protein kinases (MAPKs), and myostatin. These signaling molecules play important roles in skeletal muscle homeostasis and in a variety of inherited and acquired neuromuscular disorders. Expression of these molecules is linked to normal processes in skeletal muscle such as growth, differentiation, regeneration, and stress response. However, chronic elevation of TGF-β1, MAPKs, and myostatin is linked to various features of muscle pathology, including impaired regeneration and atrophy. In this review, we focus on the aberrant signaling of TGF-β in various disorders such as Marfan syndrome, muscular dystrophies, sarcopenia, and critical illness myopathy. We also discuss how the inhibition of several members of the TGF-β signaling pathway has been implicated in ameliorating disease phenotypes, opening up novel therapeutic avenues for a large group of neuromuscular disorders. http://www.skeletalmusclejournal.com/content/1/1/19 Tyesha Burks Ronald Cohn Skeletal Muscle 2011, null:19 2011-05-04T00:00:00Z doi:10.1186/2044-5040-1-19 /content/figures/2044-5040-1-19-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 19 2011-05-04T00:00:00Z XML In February 1961, Alexander Mauro described a cell 'wedged' between the plasma membrane of the muscle fibre and the surrounding basement membrane. He postulated that it could be a dormant myoblast, poised to repair muscle when needed. In the same month, Bernard Katz also reported a cell in a similar location on muscle spindles, suggesting that it was associated with development and growth of intrafusal muscle fibres. Both Mauro and Katz used the term 'satellite cell' in relation to their discoveries. Today, the muscle satellite cell is widely accepted as the resident stem cell of skeletal muscle, supplying myoblasts for growth, homeostasis and repair.Since 2011 marks both the 50th anniversary of the discovery of the satellite cell, and the launch of Skeletal Muscle, it seems an opportune moment to summarise the seminal events in the history of research into muscle regeneration. We start with the 19th-century pioneers who showed that muscle had a regenerative capacity, through to the descriptions from the mid-20th century of the underlying cellular mechanisms. The journey of the satellite cell from electron microscope curio, to its gradual acceptance as a bona fide myoblast precursor, is then charted: work that provided the foundations for our understanding of the role of the satellite cell. Finally, the rapid progress in the age of molecular biology is briefly discussed, and some ongoing debates on satellite cell function highlighted. http://www.skeletalmusclejournal.com/content/1/1/28 Juergen Scharner Peter Zammit Skeletal Muscle 2011, null:28 2011-08-17T00:00:00Z doi:10.1186/2044-5040-1-28 /content/figures/2044-5040-1-28-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 28 2011-08-17T00:00:00Z XML Excitation-contraction coupling involves the faithful conversion of electrical stimuli to mechanical shortening in striated muscle cells, enabled by the ubiquitous second messenger, calcium. Crucial to this process are ryanodine receptors (RyRs), the sentinels of massive intracellular calcium stores contained within the sarcoplasmic reticulum. In response to sarcolemmal depolarization, RyRs release calcium into the cytosol, facilitating mobilization of the myofilaments and enabling cell contraction. In order for the cells to relax, calcium must be rapidly resequestered or extruded from the cytosol. The sustainability of this cycle is crucially dependent upon precise regulation of RyRs by numerous cytosolic metabolites and by proteins within the lumen of the sarcoplasmic reticulum and those directly associated with the receptors in a macromolecular complex. In addition to providing the majority of the calcium necessary for contraction of cardiac and skeletal muscle, RyRs act as molecular switchboards that integrate a multitude of cytosolic signals such as dynamic and steady calcium fluctuations, β-adrenergic stimulation (phosphorylation), nitrosylation and metabolic states, and transduce these signals to the channel pore to release appropriate amounts of calcium. Indeed, dysregulation of calcium release via RyRs is associated with life-threatening diseases in both skeletal and cardiac muscle. In this paper, we briefly review some of the most outstanding structural and functional attributes of RyRs and their mechanism of regulation. Further, we address pathogenic RyR dysfunction implicated in cardiovascular disease and skeletal myopathies. http://www.skeletalmusclejournal.com/content/1/1/18 E. Michelle Capes Randall Loaiza Hector Valdivia Skeletal Muscle 2011, null:18 2011-05-04T00:00:00Z doi:10.1186/2044-5040-1-18 /content/figures/2044-5040-1-18-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 18 2011-05-04T00:00:00Z XML