In mammals, growth of the fetal heart is regulated by proliferation of cardiac muscle cells. At later stages of pre-natal life, this proliferation diminishes profoundly [1] [2] and the dramatic expansion in heart size during the transition to adulthood is due exclusively to hypertrophy of individual cardiomyocytes [3] [4] [5]. Cardiomyocyte hypertrophy also contributes to the pathology of most post-natal heart disease [6] [7] [8] [9] [10]. Within this context, numerous signal transduction pathways have been implicated as the link between the effector(s) and altered cardiac gene expression [11] [12] [13] [14] [15] [16]. A common pathway has yet to be discovered, however. Here, we found that the activity of the stress-activated kinase p38 was enhanced in both types of cardiomyocyte hypertrophy. We also found that a target of the activated p38 kinase is the cardiac transcription factor MEF2. Transgenic mice expressing a dominant-negative form of MEF2C displayed attenuated post-natal growth of the myocardium. These results provide the first evidence for a single pathway regulating both normal and pathologic cardiomyocyte hypertrophy.

Duchenne Muscular Dystrophy (DMD) originates from deleterious mutations in the dystrophin gene, with a complete loss of the protein product. Subsequently, the disease is manifested in severe striated muscle wasting and death in early adulthood. Dystrophin provides a structural base for the assembly of an integral membrane protein complex. As such, dystrophin deficiency leads to an altered mechanical integrity of the myofiber and a predisposition to contraction-induced damage. However, the development of myofiber degeneration prior to an observed mechanical defect has been documented in various dystrophic models. Although activation of a detrimental signal transduction pathway has been suggested as a probable cause, a specific cellular cascade has yet to be defined. Here, it is shown that murine models of DMD displayed a muscle-specific activation of JNK1. Independent activation of JNK1 resulted in defects in myotube viability and integrity in vitro, similar to a dystrophic phenotype. In addition, direct muscle injection of an adenoviral construct containing the JNK1 inhibitory protein, JIP1, dramatically attenuated the progression of dystrophic myofiber destruction. Taken together, these results suggest that a JNK1-mediated signal cascade is a conserved feature of dystrophic muscle and contributes to the progression of the disease pathogenesis.

Duchenne muscular dystrophy (DMD) is a progressive and ultimately fatal skeletal muscle disease. Currently, the most effective therapy is the administration of a subclass of glucocorticoids, most notably deflazacort. Although deflazacort treatment can attenuate DMD progression, extend ambulation, and maintain muscle strength, the mechanism of its action remains unknown. Prior observations have shown that activation of a JNK1-mediated signal transduction cascade contributes to the progression of the DMD phenotype, in part by phosphorylation and inhibition of a calcineurin sensitive NF-ATc1 transcription factor. Here, we observed that deflazacort treatment restored myocyte viability in muscle cells with constitutive activation of JNK1 and in dystrophic mdx mice. However, deflazacort treatment did not alter JNK1 activity itself, but rather led to an increase in the activity of the calcineurin phosphatase and an up-regulation of NF-ATc1-dependent gene expression. The prophylactic effect of deflazacort treatment was associated with increased expression of NF-ATc1 target genes such as the dystrophin homologue utrophin. Moreover, the muscle sparing effects of deflazacort were completely abolished when used in conjunction with the calcineurin inhibitor cyclosporine. Collectively, these results show that deflazacort attenuates loss of dystrophic myofiber integrity by up-regulating the activity of the phosphatase calcineurin, which in turn negates JNK1 inhibition of NF-ATc1-mediated phosphorylation and nuclear exclusion of NF-ATc1.

The TGF-beta superfamily includes a large number of related growth and differentiation factors expressed in virtually all phyla. Superfamily members bind to specific cell surface receptors that activate signal transduction mechanisms to elicit their effects. Candidate receptors fall into two primary groups, termed type I and type II receptors. Both types are serine/threonine kinases. Upon activation by the appropriate ligand, type I and type II receptors physically interact to form hetero-oligomers and subsequently activate intracellular signaling cascades, ultimately regulating gene transcription and expression. In addition, TGF-beta binds to a third receptor class, type III, a membrane-anchored proteoglycan lacking the kinase activity typical of signal transducing molecules. Type III receptors appear to regulate ligand availability to type I and type II receptors. Although a number of transduction mechanisms may be available to TGF-beta superfamily members, evidence gathered through the use of specific kinase and G-protein inhibitors and through assays measuring activation and levels of signaling intermediates suggests that at least one signaling pathway interacts with Ras and Raf proteins via a G-protein intermediate. Raf begins the cytoplasmic kinase cascade that leads to gene regulation. The myriad responses regulated by TGF-beta superfamily members makes the understanding of signal transduction mechanisms utilized by these proteins of great interest to a wide range of biological disciplines.

Muscular dystrophies are broadly classed as skeletal muscle disease entities of genetic origin. Accordingly, the development and application of gene therapy treatment modalities has focused on skeletal muscle gene replacement. Irrespective of this generalization, most forms of dystrophy are accompanied by progressive cardiomyopathy and cardiac involvement in muscular dystrophies is now recognized as an independent risk for patient morbidity. In this review, we summarize the available murine strains most suitable for modeling the dystrophic myocardium and discuss the use of adenoviral based vector systems as the preferred gene delivery vehicle for modulating dystrophic cardiomyopathy.