http://www.skeletalmusclejournal.com The most accessed research articles published by Skeletal Muscle 2012-02-07T00:00:00Z Background: Skeletal-muscle differentiation is required for the regeneration of myofibers after injury. The differentiation capacity of satellite cells is impaired in settings of old age, which is at least one factor in the onset of sarcopenia, the age-related loss of skeletal-muscle mass and major cause of frailty. One important cause of impaired regeneration is increased levels of transforming growth factor (TGF)- accompanied by reduced Notch signaling. Pro-inflammatory cytokines are also upregulated in aging, which led us hypothesize that they might potentially contribute to impaired regeneration in sarcopenia. Thus, in this study, we further analyzed the muscle differentiation-inhibition pathway mediated by pro-inflammatory cytokines in human skeletal muscle cells (HuSKMCs). Methods: We studied the modulation of HuSKMC differentiation by the pro-inflammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)- The grade of differentiation was determined by either imaging (fusion index) or creatine kinase (CK) activity, a marker of muscle differentiation. Secretion of TGF- proteins during differentiation was assessed by using a TGF--responsive reporter-gene assay and further identified by means of pharmacological and genetic inhibitors. In addition, signaling events were monitored by western blotting and reverse transcription PCR, both in HuSKMC cultures and in samples from a rat sarcopenia study. Results: The pro-inflammatory cytokines IL-1 and TNF- block differentiation of human myoblasts into myotubes. This anti-differentiation effect requires activation of TGF--activated kinase (TAK)-1. Using pharmacological and genetic inhibitors, the TAK-1 pathway could be traced to p38 and NFB. Surprisingly, the anti-differentiation effect of the cytokines required the transcriptional upregulation of Activin A, which in turn acted through its established signaling pathway: ActRII/ALK/SMAD. Inhibition of Activin A signaling was able to rescue human myoblasts treated with IL-1 or TNF-, resulting in normal differentiation into myotubes. Studies in aged rats as a model of sarcopenia confirmed that this pro-inflammatory cytokine pathway identified is activated during aging. Conclusions: In this study, we found an unexpected connection between cytokine andActivin signaling, revealing a new mechanism by which cytokines affect skeletal muscle, and establishing the physiologic relevance of this pathway in the impaired regeneration seen in sarcopenia. http://www.skeletalmusclejournal.com/content/2/1/3 Anne-Ulrike Trendelenburg Angelika Meyer Carsten Jacobi Jerome Feige David Glass Skeletal Muscle 2012, null:3 2012-02-07T00:00:00Z doi:10.1186/2044-5040-2-3 /content/figures/2044-5040-2-3-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 3 2012-02-07T00:00:00Z 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 No description available http://www.skeletalmusclejournal.com/content/2/1/1 David Glass Kevin Campbell Michael Rudnicki Skeletal Muscle 2012, null:1 2012-01-05T00:00:00Z doi:10.1186/2044-5040-2-1 /content/figures/2044-5040-2-1-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 1 2012-01-05T00:00:00Z PDF Background: Muscle atrophy associated with various pathophysiological conditions represents a major health problem, due to its contribution to the deterioration of patient status and its impact on mortality. Although the involvement of pro-inflammatory cytokines in this process is well-recognized, the role of sphingolipid metabolism alterations induced by the cytokines has received little attention. Results: We addressed this question both in vitro, using differentiated myotubes treated by TNFalpha, and in vivo, in a murine model of tumor-induced cachexia. Myotube atrophy induced by TNFalpha was accompanied by a substantial increase in cell ceramide levels, and could be mimicked by the addition of exogenous ceramides. It could be prevented by the addition of ceramide synthesis inhibitors that targeted either the de novo pathway (myriocin), or sphingomyelinases (GW4869 and 3-O-methylsphingomyelin). In the presence of TNFalpha, ceramide synthesis inhibitors significantly increased protein synthesis and decreased proteolysis. In parallel, they lowered the expression of both Atrogin-1 and LC3b genes, respectively involved in muscle protein degradation by proteasome, and autophagic proteolysis, and increased the proportion of inactive, phosphorylated Foxo3 transcription factor. Furthermore, these inhibitors increased the expression and/or phosphorylation levels of key factors regulating protein metabolism, including phospholipase D, an activator of mTOR, and the mTOR substrates S6K1 and Akt. In vivo, C26 carcinoma implantation induced a substantial increase of muscle ceramide, together with drastic muscle atrophy. Treatment of the animals by myriocin reduced the expression of atrogenes Foxo3 and Atrogin-1, and partially protected muscle tissue from atrophy. Conclusions: These results indicate that ceramide accumulation induced by TNFalpha or tumor development participates in the mechanism of muscle cell atrophy, and that sphingolipid metabolism can be a relevant target for pharmacological or nutritional interventions aiming at preserving muscle mass in pathological situations. http://www.skeletalmusclejournal.com/content/2/1/2 Joffrey De Larichaudy Alessandra Zufferli Filippo Serra Andrea Isidori Fabio Naro Kevin Dessalle Marine Desgeorges Monique Piraud David Cheillan Hubert Vidal Etienne Lefai Georges Nemoz Skeletal Muscle 2012, null:2 2012-01-18T00:00:00Z doi:10.1186/2044-5040-2-2 /content/figures/2044-5040-2-2-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 2 2012-01-18T00:00:00Z 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: Myogenic differentiation involves cell-cycle arrest, activation of the muscle-specific transcriptome, and elongation, alignment and fusion of myoblasts into multinucleated myotubes. This process is controlled by promyogenic transcription factors and regulated by signaling pathways in response to extracellular cues. The p38 mitogen-activated protein kinase (p38 MAPK) pathway promotes the activity of several such transcription factors, including MyoD and MEF2, thereby controlling the muscle-specific transcription program. However, few p38-regulated genes that play a role in the regulation of myogenesis have been identified. Methods: RNA interference (RNAi), chemical inhibition and immunofluorescence approaches were used to assess the role of drebrin in differentiation of primary mouse myoblasts and C2C12 cells. Results: In a search for p38-regulated genes that promote myogenic differentiation, we identified Dbn1, which encodes the actin-binding protein drebrin. Drebrin is an F-actin side-binding protein that remodels actin to facilitate the change of filopodia into dendritic spines during synaptogenesis in developing neurons. Dbn1 mRNA and protein are induced during differentiation of primary mouse and C2C12 myoblasts, and induction is substantially reduced by the p38 MAPK inhibitor SB203580. Primary myoblasts and C2C12 cells depleted of drebrin by RNAi display reduced levels of myogenin and myosin heavy chain and form multinucleated myotubes very inefficiently. Treatment of myoblasts with BTP2, a small-molecule inhibitor of drebrin, produces a phenotype similar to that produced by knockdown of drebrin, and the inhibitory effects of BTP2 are rescued by expression of a mutant form of drebrin that is unable to bind BTP2. Drebrin in myoblasts is enriched in cellular projections and cell cortices and at regions of cell-cell contact, all sites where F-actin, too, was concentrated. Conclusions: Our findings reveal that Dbn1 expression is a target of p38 MAPK signaling during myogenesis and that drebrin promotes myoblast differentiation. http://www.skeletalmusclejournal.com/content/1/1/36 Annalisa Mancini Dario Sirabella Weijia Zhang Hiroyuki Yamazaki Tomoaki Shirao Robert Krauss Skeletal Muscle 2011, null:36 2011-12-08T00:00:00Z doi:10.1186/2044-5040-1-36 /content/figures/2044-5040-1-36-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 36 2011-12-08T00:00:00Z XML 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: Investigations into both the pathophysiology and therapeutic targets in muscle dystrophies have been hampered by the limited proliferative capacity of human myoblasts. Isolation of reliable and stable immortalized cell lines from patient biopsies is a powerful tool for investigating pathological mechanisms, including those associated with muscle aging, and for developing innovative gene-based, cell-based or pharmacological biotherapies. Methods: Using transduction with both telomerase-expressing and cyclin-dependent kinase 4-expressing vectors, we were able to generate a battery of immortalized human muscle stem-cell lines from patients with various neuromuscular disorders. Results: The immortalized human cell lines from patients with Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, congenital muscular dystrophy, and limb-girdle muscular dystrophy type 2B had greatly increased proliferative capacity, and maintained their potential to differentiate both in vitro and in vivo after transplantation into regenerating muscle of immunodeficient mice. Conclusions: Dystrophic cellular models are required as a supplement to animal models to assess cellular mechanisms, such as signaling defects, or to perform high-throughput screening for therapeutic molecules. These investigations have been conducted for many years on cells derived from animals, and would greatly benefit from having human cell models with prolonged proliferative capacity. Furthermore, the possibility to assess in vivo the regenerative capacity of these cells extends their potential use. The innovative cellular tools derived from several different neuromuscular diseases as described in this report will allow investigation of the pathophysiology of these disorders and assessment of new therapeutic strategies. http://www.skeletalmusclejournal.com/content/1/1/34 Kamel Mamchaoui Capucine Trollet Anne Bigot Elisa Negroni Soraya Chaouch Annie Wolff Prashanth Kandalla Solenne Marie James Di Santo Jean Lacau St Guily Francesco Muntoni Jihee Kim Susanne Philippi Simone Spuler Nicolas Levy Sergiu Blumen Thomas Voit Woodring Wright Ahmed Aamiri Gillian Butler-Browne Vincent Mouly Skeletal Muscle 2011, null:34 2011-11-01T00:00:00Z doi:10.1186/2044-5040-1-34 /content/figures/2044-5040-1-34-toc.gif Skeletal Muscle 2044-5040 ${item.volume} 34 2011-11-01T00:00:00Z 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 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