The cardiac troponin C mutation Leu29Gln found in a patient with hypertrophic cardiomyopathy does not alter contractile parameters in skinned murine myocardium

The present study investigates the effects of the first mutation of troponin C (hcTnCL29Q) found in a patient with hypertrophic cardiomyopathy (HCM) on force–pCa relations and the interplay with phosphorylation of sarcomeric PKA substrates. In triton-skinned murine cardiac fibers, the endogenous mcTnC was extracted and the fibers were subsequently reconstituted with recombinant wild-type and mutant hcTnC. Force–pCa relations of preparations containing hcTnCL29Q or hcTnCWT were similar. Incubation of fibers reconstituted with the recombinant proteins with phosphatase to dephosphorylate sarcomeric PKA substrates induced an increase in Ca2+ sensitivity, slightly more pronounced (0.04 pCa units) in hcTnCL29Q-containing fibers. Incubation of the dephosphorylated fibers with PKA induced significant rightward shifts of force–pCa relations of similar magnitude with both, hcTnCL29Q and hcTnCWT. No significant effects of hcTnCL29Q on the velocity of unloaded shortening were observed. In conclusion, no major differences in contractile parameters of preparations containing hcTnCL29Q compared to hcTnCWT were observed. Therefore, it appears unlikely that hcTnCL29Q induces the development of HCM by affecting the regulation of Ca2+-activated force and interference with PKA-mediated modulation of the Ca2+ sensitivity of contraction

TRAF6 Promotes Myogenic Differentiation via the TAK1/p38 Mitogen-Activated Protein Kinase and Akt Pathways

p38 mitogen-activated protein kinase (MAPK) is an essential kinase involved in myogenic differentiation. Although many substrates of p38 MAPK have been identified, little is known about its upstream activators during myogenic differentiation. TRAF6 is known to function in cytokine signaling during inflammatory responses. However, not much is known about its role in myogenic differentiation and muscle regeneration. We showed here that TRAF6 and its intrinsic ubiquitin E3 ligase activity are required for myogenic differentiation. In mouse myoblasts, knockdown of TRAF6 compromised the p38 MAPK and Akt pathways, while deliberate activation of either pathway rescued the differentiation defect caused by TRAF6 knockdown. TAK1 acted as a key signal transducer downstream of TRAF6 in myogenic differentiation. In vivo, knockdown of TRAF6 in mouse muscles compromised the injury-induced muscle regeneration without impairing macrophage infiltration and myoblast proliferation. Collectively, we demonstrated that TRAF6 promotes myogenic differentiation and muscle regeneration via the TAK1/p38 MAPK and Akt pathways

Cause-specific mortality in a cohort of patients with diabetes mellitus:A population-based study in Sweden

A cohort of patients with diabetes mellitus hospitalised in Sweden from 1965 to 1983 was followed up until 1989, by linkages of population-based registers. Standardised mortality ratios (SMR), adjusted for confounding variables, and 95% confidence intervals (CIs) were calculated. After exclusion of the first year of follow-up (to reduce the effect of selection bias), the cohort consisted of 144,427 patients, of whom 92,248 patients died during follow-up. The SMR for all causes of death combined was 2.62 (95% CI 2.58- 2.67) among men and 3.23 (95% CI 3.18-3.28) among women. The excess mortality was still evident 20 years after first hospitalisation. but became less marked with longer follow-up time. Patients with presumably insulin-dependent diabetes mellitus (IDDM) had the highest SMRs (10.2: CI 9.5-11.0); however, there was a significant (34%) improvement over time in their mortality risk. We conclude that excess mortality persisted throughout all calendar periods and at all ages, indicating the need for health care prevention measures. (C) 2001 Elsevier Science Inc. All rights reserved

Role for phosphodiesterase 3B in regulation of lipolysis and insulin secretion

Thoroughly revised and updated, this Third Edition encompasses the most recent advances in molecular and cellular research and describes the newest therapeutic modalities for type 1 and type 2 diabetes mellitus. Chapters by leading experts integrate the latest basic science and clinical research on diabetes mellitus and its complications. The text is divided into ten major sections, including extensive sections on therapeutics, diabetes during pregnancy, and complications. New chapters cover stem cell therapy for type 1 diabetes; genetics and treatment of obesity; new therapies to promote insulin action; vasculopathy; islet cell protocols; triglycerides in muscle; hypoglycemia in the adult; and the Diabetes Prevention Program

Induction of the Synthesis of Melanin and Pteridine in Cells Isolated from the Axolotl Embryo: induction/melanin/pteridine/embryonic cells/axolotl

It has previously been reported that when LiCl and tyrosine is added to ectodermal cells isolated from the blastula of Ambystoma mexicanum, then the synthesis of melanin is initiated in cells not normally engaged in this activity (mesenchyme cells, nerve cells and undifferentiated animal cells). In the present paper it has been shown that to obtain this effect tyrosine (0.02 mM) has to be present in the culture medium during at least one of the first seven days of culture, thus several days before melanin is produced. It is concluded that the added tyrosine is acting as an inductor of, and not as a substrate for the synthesis of melanin. In the normal cultures it is possible to observe the spontaneous formation of yellow cells, indicating that they have produced pteridine. These cells are spherical, suggesting that they are undifferentiated embryonic cells. GTP is a precursor in the synthesis of pteridine, and in analogy with the observations made with tyrosine it was found that in the presence of LiCl a number of different cell types elaborate pteridine when GTP (0.1 mM) is added to the medium. Also in this case was it possible to show that GTP acts as an inductor, not as a substrate. Copyright © 1984, Wiley Blackwell. All rights reserve