Elizabeth McNally

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..The characterization of epsilon-sarcoglycan should make it possible to determine if it, like the other sarcoglycan genes, is mutated in muscular dystrophy...

..A subset of muscular dystrophies may place patients at significantly greater risk of developing cardiomyopathy and cardiac rhythm disturbances. These disorders are discussed, highlighting recent studies and recommendations for therapy...

..This chapter reviews the basic structural properties of muscle and genetic mechanisms that lead to myopathy and muscular dystrophies that affect all age groups...

..These therapies are expected to also improve the cardiac function, longevity and wellbeing of muscular dystrophy patients...

..In this review, we will examine the genetic defects that lead to cardiomyopathy and the potential means by which these varied proteins normally maintain the structural integrity of myocytes...

..The amino acid changes map to a functionally important domain in caveolin-3, suggesting that these are not benign polymorphisms and instead are disease-causing mutations...

..This mutation produced an absence of normal dysferlin mRNA synthesis by affecting an acceptor site and cryptic splicing. Thus, splice site mutations that disrupt dysferlin may produce a phenotype associated with inflammation...

..Vascular reactivity is altered in response to primary degeneration in striated myocytes and arises from a vascular smooth muscle cell-extrinsic mechanism...

..The nuclear lamina is thought to regulate gene expression by its direct interaction with chromatin. LMNA gene mutations may mediate disease by disrupting normal gene expression...

..In the current study, we tested the hypothesis that S100A12 expressed in vascular smooth muscle in atherosclerosis-prone apolipoprotein E (ApoE)-null mice would accelerate atherosclerosis...

..RAGE has been extensively implicated in inflammatory states such as atherosclerosis, but the role of S100A12 as its ligand is less clear...

..We studied the role of NO signaling on cardiovascular outcomes following cardiac arrest and resuscitation using endothelial NO synthase knockout (NOS3(-/-)) mice...

..Collectively, these findings significantly advance our understanding of exercise-induced muscle fatigue and its role in muscle disease...

..Identification of these modifier genes and the associated pathways may lead to novel therapeutic strategies...

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..In contrast, a 12-amino-acid deletion in LTBP4 was associated with increased proteolysis, SMAD signaling, and fibrosis. These data identify Ltbp4 as a target gene to regulate TGF-beta signaling and modify outcomes in muscular dystrophy...

..This review discusses the cellular mechanisms that are primarily and secondarily disrupted in muscular dystrophy, focusing on membrane degeneration, muscle regeneration, and the repair of muscle...

..These findings demonstrate the role of the LINC complex, and nesprin-1, in neuromuscular and cardiac disease...

..Together, these data demonstrate the essential nature of the transmembrane and extracellular domains of Drosophila delta-sarcoglycan for normal muscle structure and function...

..Normal sarcolemmal function requires proper DGC synthesis and positioning, and perturbation of the DGC leads to muscle membrane instability and disease...

..Nitric oxide synthase and stress-induced signaling cascades are activated to participate in protection but may also contribute to pathology...

..Myoferlin modulates the response to muscle injury through its activity in both myoblasts and mature myofibers...

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..We propose that membrane-anchored nesprin-1alpha antiparallel dimers interact with both emerin and lamin A to provide scaffolding at the inner nuclear membrane...

..Therefore, we propose that cytokine release from damaged cardiomyocytes can feed back to produce vascular spasm. Moreover, vascular spasm feeds forward to produce additional cardiac damage...

..30 ml/minute/g versus 0.67 +/- 0.16 ml/minute/g, P < 0.05). These data indicate that secondary vasospasm contributes to the development of cardiomyopathy and is an important therapeutic target to limit cardiomyopathy progression...

..Based on these data, we propose a mechanism for muscular dystrophy in which calcium-regulated phospholipid binding is abnormal, leading to defective maintenance and repair of muscle membranes...

..These data provide a mechanism where regional, focal cardiac damage creates pathologic gradients of NO. Moreover, inhibition of nitric oxide synthase corrects defects that arise from pathologic NO gradients...

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..The critical function of this deubiquitinating enzyme in the restriction of TLR signals emphasizes the importance of the regulation of ubiquitin conjugation in innate immune cells...

..These human genetic findings support that normal myocardial and sarcomere function are required for proper compaction and septation and that these mutations also portend a high risk of developing heart failure in later life...

..Despite an improved response to acute sympathetic stress and baseline cardioprotection, exercise intolerance results from lack of SUR2 K(ATP) channels in mice...

..Demonbreun, A. R., Posey, A. D., Heretis, K., Swaggart, K. A., Earley, J. U., Pytel, P., McNally, E. M. Myoferlin is required for insulin-like growth factor response and muscle growth...

..We sought to further define the role of sarcomere mutations in dilated cardiomyopathy (DCM) and associated clinical phenotypes...

..The muscle-specific inner nuclear envelope expression of myne-1, along with its interaction with lamin A/C, indicates that this gene is a potential mediator of cardiomyopathy and muscular dystrophy...

..Family history questionnaires in cardiology clinics can be a cost-effective tool for identifying patients and families who are in the greatest need of genetic evaluation and genetic counseling services...

..These data support a role for myoferlin in the maturation of myotubes and the formation of large myotubes that arise from the fusion of myoblasts to multinucleate myotubes...

..The interaction of myoferlin with EHD2 identifies molecular overlap between the endocytic recycling pathway and the machinery that regulates myoblast membrane fusion...

..The purpose of this research was to determine the phenotypic spectrum associated with phospholamban gene (PLN) mutations...

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..Recent evidence suggests that disruption of the smooth muscle sarcoglycan complex is not required for the development of vascular spasm and that vascular spasm arises from a vascular smooth muscle cell-extrinsic process...

..Together, these data demonstrate that zeta-sarcoglycan is an integral component of the sarcoglycan complex and, as such, is important in the pathogenesis of muscular dystrophy...

..The intermittent coronary artery vasospasm seen in Sur2(-/-) mice provides a model for the human disorder Prinzmetal variant angina and demonstrates that the SUR2 K(ATP) channel is a critical regulator of episodic vasomotor activity...

..These findings mirror what has been described from lamin A/C gene mutations and reinforce the importance of an intact nuclear membrane complex for a normally functioning heart...

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..The value of these genes and products is that the pathways identified through these experiments may be exploited for therapy...

..Therefore, cardioprotective mechanisms both dependent and independent of SUR2-K(ATP) channels contribute to cardiac function...

..We conclude that spontaneous coronary vasospasm and sudden death in SUR2 null mice arises from a coronary artery vascular smooth muscle-extrinsic process...

..Cardioprotective pathways may involve a mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel but its composition is not fully understood...

..The inability of BM-SP cells to express this protein severely limits their utility for cardiac and skeletal muscle regeneration...

..We conclude that conventional sarcolemmal cardiomyocyte K(ATP) channels containing full-length SUR2 are not required for mediating the response to acute cardiovascular stress...

..These data are the first to report novel biological activities for myoferlin and reveal the role of membrane integrity to VEGF signaling...

..These findings suggest that MSTN inhibition may benefit muscular dystrophy when instituted early or if disease is relatively mild but that MSTN inhibition in severely affected or late-stage disease may be ineffective...

..In turn, overexpression of these spectrin repeat domains in myocytes can displace mAKAP from nesprin-1alpha...

..Our results suggest that inhibition of Cn may benefit select types of muscular dystrophy...

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..In addition, there will be two poster sessions. Trainees are strongly encouraged to attend and participate. ..

..These findings will improve our understanding of the cellular defects in muscular dystrophy and cardiomyopathy and may help devise new strategies for therapy. ..

..The training program is directed by Elizabeth McNally, M.D., Ph.D. Dr. McNally is an Associate Professor who serves as the Director of Cardiovascular Research. Dr...

..We will also study the role of cardiac and vascular smooth muscle KATP channels in mediating the response to acute adrenergically mediated stress. ..

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..Understanding this pathway will guide the design of new therapies to promote muscle growth and repair in disease and aging. ..

..My laboratory is interesting in determining how changing the nuclear membrane leads to muscle disease. ..

..Understanding this pathway will guide the design of new therapies to promote muscle growth and repair in disease and aging. ..

..Significance: These experiments are designed to improve our understanding membrane fusion in muscle. Membrane fusion in muscle is relevant to diseases such as muscular dystrophy and also to the normal aging process of muscle. ..

..By developing genetic markers, we will identify those at risk for arrhythmia and most like to benefit from pacemaker and/or implantable defibrillator treatment. ..

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..Together, these experiments will outline the temporal profile of gene expression changes that arise in these disorders. ..

..The small format and topic of this meeting is unique and will allow senior and junior investigators along with trainees to interact productively in an exchange of information. ..

..We are conducting genetic studies to identify genes that improve muscular dystrophy because knowing these regions will help us predict better how patients will fare and also because these regions may point to new pathways for therapy. ..