HUGH SWEENEY

..In addition, the rate of ATP hydrolysis is slowed...

..Furthermore, these data suggest that these TnT mutations may cause disease via an increased energetic load on the heart. This would represent a second paradigm for HCM pathogenesis...

..This may be part of the mechanism underlying "latch" in smooth muscle...

..These mechanistic insights allow us to speculate on how unusual aspects of myosin VI structure and function allow it to fill unique niches in cells...

..We also describe studies that delineate how some classes of myosin motors are adapted for processive movement on actin...

..Given that other classes of myosins may share some of these features, understanding the design principles of myosin VI will help guide the study of the functions of myosins that adopt similar strategies...

..Previously described approaches to blocking myostatin signaling include injection delivery of inhibitory propeptide domain or neutralizing antibodies...

..This study shows that progenitor cells can be genetically engineered in vivo and subsequently proliferate into terminally differentiated tissue carrying the genetic graft in a way that stably corrects function...

..These studies show that, unlike limb muscles, the diaphragm from the A/J mouse displays early deficits in function that may lower the age needed for evaluating potential therapies for dysferlinopathies...

..This technique may be useful to treat or prevent postinfarction heart failure...

..Myostatin is a negative regulator of cardiac growth, and further studies are warranted to investigate the role of myostatin in the healthy and failing heart...

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..No effect on heart mass or function was observed. Our results indicate that activin IIB receptor blockade represents a novel and effective therapeutic strategy for the muscular dystrophies...

..AAV9 should be used in rodent cardiac studies and may be the vector of choice for clinical trials of cardiac gene transfer...

..g., calcium metabolism, apoptosis) could normalize diseased myocardial function. Gene therapy may offer a promising new approach for the treatment of cardiac disease in both veterinary and human clinical settings...

..The authors are currently evaluating this approach to treat canine idiopathic dilated cardiomyopathy...

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..Adenovirus-apoptosis repressor with caspase recruitment domain administration offers a potential strategy after myocardial ischemia to protect the heart from late postischemic cardiomyopathy...

..This study examined the feasibility of AAV-mediated myocardial gene transfer in mice, the animal which, because of transgenic technology, has become the disease model of choice for cardiovascular research...

..The benefit at 6 weeks is postulated to result from a Bcl-2-mediated reduction in apoptosis and ventricular remodeling. Adeno-Bcl-2 administration offers a potential strategy to protect the heart from late postischemic heart failure...

..Lastly, calmodulin mutants reveal that the calcium effect is dependent on calcium binding to the N-terminal lobe of calmodulin...

..While this mechanism is unlike that of any other myosin superfamily member, it bears remarkable similarities to that of another processive motor from a different superfamily--kinesin I...

..The ability to maintain a high affinity for actin in the weak binding states may prevent diffusion away from the actin filament and increase the degree of processive motion of myosin V...

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..These effects are likely mediated by binding of blebbistatin within the myosin cleft that progressively closes in forming the acto-myosin rigor state...

..These results suggest that a combination of promoting muscle regenerative capacity and preventing muscle necrosis could be an effective treatment for the secondary symptoms caused by the primary loss of dystrophin...

..The reduction in myocardial fibrosis may be primarily responsible for the improved diastolic function in treated animals. TIMP-1 overexpression is a promising therapeutic target for continued investigation...

..Thus BBI is a candidate therapeutic agent to minimize skeletal muscle atrophy and loss of strength associated with disuse, cachexia, sepsis, weightlessness, or the combination of age and inactivity...

..Myotubes in culture are thus clearly prestressed by myosin II, and this contractility couples to substrate compliance and ultimately influences actomyosin striation...

..Because, unexpectedly, a monomeric fragment of Dab2 triggers dimerization, it would appear that myosin VI is designed to function as a dimer in cells...

..We conclude that gammaSG normally moderates contractile prestress in skeletal muscle, and we propose a role for gammaSG in membrane-based signaling of the effects of prestress and sarcomerogenesis...

..This therapy may be useful as an adjunct or alternative to standard revascularization techniques in patients with ischemic heart failure...

..This unconventional mechanism generates an extension of the lever arm of myosin VI...

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..0369). CONCLUSIONS: The administration of the glycolytic intermediate, FDP, by intravenous injection, resulted in significantly improved myocardial function after ischemia and improved bioenergetics during ischemia...

..Furthermore, they suggest that high-throughput screens to identify regulators of cancer cell invasion may be feasible in zebrafish...

..These findings have major implications for in vivo introduction of stem cells into diseased or damaged striated muscle of altered mechanical composition...

..The results thus reveal new modes of dystrophin flexibility that may prove central to functions of both dystrophin and mini-dystrophins...

..05) and the relaxation time constant (14.6 +/- 0.6 vs 17.9 +/- 1.2 msec; p < 0.05). CONCLUSIONS: TNF inhibition after infarction reduced leukocyte infiltration and extracellular matrix turnover and preserved cardiac function...

..Improving scarred heart muscle compliance could be a functional benefit of cellular cardiomyoplasty...

..We propose that the regulated dimerization obviates the need to regulate motor activity. ..

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..determine which kinetic and structural features are necessary for processive movement and the large step size of myosin VI; and 3) delineate putative modes of regulation of the myosin VI motor. ..

..This will be a transitional conference in that the overall focus of the conference will be divided between the Molecular Basis of Muscle Contraction and the broader topic of the Design and Function of Molecular Motors. ..

..Lee Sweeney, Ph.D.); and Section 3: development of non-invasive methods for monitoring therapeutic benefits of dystrophin gene transfer (directed by Glenn Walter, Ph.D.). ..

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..We propose that the regulated dimerization obviates the need to regulate motor activity. ..

..Its foci on cellular and molecular aspects of skeletal muscle as they relate to health, disease and dysfunction should bring together researchers who do not often attend the same meetings. ..

..Plasticity is relevant not only to normal adaptation to altered activity but also to adaptation that occurs in neuromuscular disease states...

..In addition, proteins will be through a combination of heterologous expression using either baculovirus/SF9 cells or E. coli and through the purification of proteins from rabbit tissues. ..

..This is evidenced by the many prominent scientists around the world, who have trained in this field at the University of Pennsylvania. ..

..In this manner we will begin to dissect the functional and structural domains of the myosin motor, within the framework of delineating the principles of myosin design and isoform diversity. ..

..Our findings will provide fundamental knowledge of the mechanisms of muscle contraction and a basis for development of gene and drug therapies for the treatment of HCM. ..