Activation of JNK1 contributes to dystrophic muscle pathogenesis.

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.

MEF2 is upregulated during cardiac hypertrophy and is required for normal post-natal growth of the myocardium.

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.

Signal transduction and TGF-beta superfamily receptors.

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.

[Lipoprotein lipase in the blood and cerebrospinal fluid of patients with multiple sclerosis]. / Aktywnosc lipazy lipoproteinowej we krwi i w plynie mózgowo-rdzeniowym chorych na stwardnienie rozsiane.

The authors determined the activity of lipoprotein lipase in the blood and cerebrospinal fluid in 25 patients with exacerbation of multiple sclerosis and in 20 controls. A significant decrease in the activity of the enzyme was found in blood of the patients, while only trace activity was detected in the cerebrospinal fluid in both groups. The significant decrease of lipoprotein lipase activity in blood of patients the with multiple sclerosis requires further investigations.

[Serum content of alpha-amino nitrogen in patients with stroke]. / Zawartosc azotu alfa-aminowego w surowicy krwi chorych z udarem mózgu

The concentration of alpha-amino nitrogen in the serum of 18 healthy subjects, 17 patients with cerebral haemorrhage, and 23 patients with encephalomalacia due to thrombosis was determined by the colorimetric ninhydrin method of Moore and Stein modified by Slavik. The determinations were done on the 1st, 3rd and 10th days of the disease. The mean concentration of alpha-amino nitrogen in the serum of patients with cerebral haemorrhage was lower than in controls on the 1st and 3rd days of the disease but the difference was not significant statistically. The mean level of alpha-amino nitrogen in the serum of patients with encephalomalacia was lower on the 1st day than in controls while on the 3rd and 10th day it was slightly higher as compared with controls, however, statistically the differences were not significant. The mean values of alpha-amino nitrogen in the serum of patients with cerebral haemorrhage and those with encephalomalacia gradually approached the control values.

[Catalase-like activity in cerebrospinal fluid in patients with cerebral stroke]. / Aktywnosc katalazopodobna w plynie mózgowo-rdzeniowym chorych z udarem mózgu

Catalase-like activity was determined in the cerebrospinal fluid of 16 patients with cerebral haemorrhage, 24 cases od encephalomalacia due to thrombosis, and 10 controls. It was demonstrated that catalase-like activity in the cerebrospinal fluid of patients with cerebral stroke is significantly raised in relation to the activity observed in controls. This rise is patricularly evident in the first 24 hours after the onset. The rise was statistically significant only in the group of encephalomalacia.