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Duchenne muscular dystrophy (DMD) is a severe, progressive, and ultimately fatal disease of skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. The identification of the dystrophin gene as central to DMD pathogenesis has led to the understanding of the muscle membrane and the proteins involved in membrane stability as the focal point of the disease. The lessons learned from decades of research in human genetics, biochemistry, and physiology have culminated in establishing the myriad functionalities of dystrophin in striated muscle biology. Here, we review the pathophysiological basis of DMD and discuss recent progress toward the development of therapeutic strategies for DMD that are currently close to or are in human clinical trials. The first section of the review focuses on DMD and the mechanisms contributing to membrane instability, inflammation, and fibrosis. The second section discusses therapeutic strategies currently used to treat DMD. This includes a focus on outlining the strengths and limitations of approaches directed at correcting the genetic defect through dystrophin gene replacement, modification, repair, and/or a range of dystrophin-independent approaches. The final section highlights the different therapeutic strategies for DMD currently in clinical trials. [ABSTRACT FROM AUTHOR]

EF-hand proteins are ubiquitous in cell signaling. Parvalbumin (Parv), the archetypal EF-hand protein, is a high-affinity [Ca.sup.2+] buffer in many biological systems. Given the centrality of [Ca.sup.2+] signaling in health and disease, EF-hand motifs designed to have new biological activities may have widespread utility. Here, an EF-hand motif substitution that had been presumed to destroy EF-hand function, that of glutamine for glutamate at position 12 of the second cation binding loop domain of Parv (ParvE101Q), markedly inverted relative cation affinities: [Mg.sup.2+] affinity increased, whereas [Ca.sup.2+] affinity decreased, forming a new ultra-delayed [Ca.sup.2+] buffer with favorable properties for promoting cardiac relaxation. In therapeutic testing, expression of ParvE101Q fully reversed the severe myocyte intrinsic contractile defect inherent to expression of native Parv and corrected abnormal myocardial relaxation in diastolic dysfunction disease models in vitro and in vivo. Strategic design of new EF-hand motif domains to modulate intracellular [Ca.sup.2+] signaling could benefit many biological systems with abnormal [Ca.sup.2+] handling, including the diseased heart., Calcium ([Ca.sup.2+]) is a ubiquitous intracellular second messenger that participates in diverse intracellular processes ranging from muscle contraction to gene expression and cell survival (1). In the heart, rapid release [...]

Treatment of rodents with a bombesin receptor subtype-3 (BRS-3) agonist reduces food intake and increases fasting metabolic rate, causing weight loss with continued treatment. In small mammals, core body temperature ([T.sub.b]) is regulated in part by nutritional status, with a reduced [T.sub.b] during fasting. We report that fed Brs3 knockout mice have a lower [T.sub.b], which is discordant with their nutritional status. Treatment of wild-type mice with a BRS-3 agonist increased [T.sub.b], more so when the baseline [T.sub.b] was reduced such as by fasting or during the inactive phase of the light cycle. With repeated BRS-3 agonist dosing, the [T.sub.b] increase attenuated despite continued weight loss efficacy. The increase in [T.sub.b] was not prevented by inhibitors of prostaglandin E (PGE) production but was partially reduced by a [beta]-adrenergic blocker. These results demonstrate that BRS-3 has a role in body temperature regulation, presumably secondary to its effect on energy metabolism, including effects on sympathetic tone. By making use of this phenomenon, the reversal of the fasting [T.sub.b] reduction was developed into a sensitive single-dose pharmacodynamic assay for BRS-3 agonism and other antiobesity compounds acting by various mechanisms, including sibutramine, cannabinoid-1, and melanin-concentrating hormone-1 receptor blockers, and melanocortin, [[beta].sub.3]-adrenergic, and cholecystokinin-1 receptor agonists. These drugs increased both the fasted [T.sub.b] and the fasted, resting metabolic rates. The [T.sub.b] assay is a robust, information-rich assay that is simpler and has a greater throughput than measuring metabolic rate and is a practical, effective tool for drug discovery. tachyphylaxis; metabolic rate; thermoregulation; fasting; drug discovery doi: 10.1152/ajpendo.00404.2010.

Duchenne muscular dystrophy (DMD) is a fatal disease of striated muscle deterioration caused by lack of the cytoskeletal protein dystrophin. Dystrophin deficiency causes muscle membrane instability, skeletal muscle wasting, cardiomyopathy, and heart failure. Advances in palliative respiratory care have increased the incidence of heart disease in DMD patients, for which there is no cure or effective therapy. Here we have shown that chronic infusion of membrane-sealing poloxamer to severely affected dystrophic dogs reduced myocardial fibrosis, blocked increased serum cardiac troponin I (cTnI) and brain type natriuretic peptide (BNP), and fully prevented left-ventricular remodeling. Mechanistically, we observed a markedly greater primary defect of reduced cell compliance in dystrophic canine myocytes than in the mildly affected mdx mouse myocytes, and this was associated with a lack of utrophin upregulation in the dystrophic canine cardiac myocytes. Interestingly, after chronic poloxamer treatment, the poor compliance of isolated canine myocytes remained evident, but this could be restored to normal upon direct application of poloxamer. Collectively, these findings indicate that dystrophin and utrophin are critical to membrane stability-dependent cardiac myocyte mechanical compliance and that poloxamer confers a highly effective membrane-stabilizing chemical surrogate in dystro-phin/utrophin deficiency. We propose that membrane sealant therapy is a potential treatment modality for DMD heart disease and possibly other disorders with membrane defect etiologies., Introduction Duchenne muscular dystrophy (DMD) is a devastating progressive disease of striated muscle deterioration that results from the loss of the protein dystrophin (1), (2). Most patients with DMD develop [...]