The small molecule SERCA activator CDN1163 increases energy metabolism in human skeletal muscle cells.

BACKGROUND AND OBJECTIVE: A number of studies have highlighted muscle-specific mechanisms of thermogenesis involving futile cycling of Ca2+ driven by sarco (endo)plasmic reticulum Ca2+-ATPase (SERCA) and generating heat from ATP hydrolysis to be a promising strategy to counteract obesity and metabolic dysfunction. However, to the best of our knowledge, no experimental studies concerning the metabolic effects of pharmacologically targeting SERCA in human skeletal muscle cells have been reported. Thus, in the present study, we aimed to explore the effects of SERCA-activating compound, CDN1163, on energy metabolism in differentiated human skeletal muscle cells (myotubes). METHODS: In this study, we used primary myotube cultures derived from muscle biopsies of the musculus vastus lateralis and musculi interspinales from lean, healthy male donors. Energy metabolism in myotubes was studied using radioactive substrates. Oxygen consumption rate was assessed with the Seahorse XF24 bioanalyzer, whereas metabolic genes and protein expressions were determined by qPCR and immunoblotting, respectively. RESULTS: Both acute (4 â€‹h) and chronic (5 days) treatment of myotubes with CDN1163 showed increased uptake and oxidation of glucose, as well as complete fatty acid oxidation in the presence of carbonyl cyanide 4-(trifluromethoxy)phenylhydrazone (FCCP). These effects were supported by measurement of oxygen consumption rate, in which the oxidative spare capacity and maximal respiration were enhanced after CDN1163-treatment. In addition, chronic treatment with CDN1163 improved cellular uptake of oleic acid (OA) and fatty acid ß-oxidation. The increased OA metabolism was accompanied by enhanced mRNA-expression of carnitine palmitoyl transferase (CPT) 1B, pyruvate dehydrogenase kinase (PDK) 4, as well as increased AMP-activated protein kinase (AMPK)Thr172 phosphorylation. Moreover, following chronic CDN1163 treatment, the expression levels of stearoyl-CoA desaturase (SCD) 1 was decreased together with de novo lipogenesis from acetic acid and formation of diacylglycerol (DAG) from OA. CONCLUSION: Altogether, these results suggest that SERCA activation by CDN1163 enhances energy metabolism in human myotubes, which might be favourable in relation to disorders that are related to metabolic dysfunction such as obesity and type 2 diabetes mellitus.

Burden of Cancers in Iran from 1990 to 2010: findings from the Global Burden of Disease study 2010.

BACKGROUND: Cancer is one of the most common non-communicable diseases in both sexes and a major cause of disability and death around the world, as well as in Iran. The aim of the present manuscript is to report the results of the Global Burden of Disease study 2010 (the GBD 2010) to compare the results with the other similar findings. The paper also discusses the existing deficiencies of the GBD study. Our aim was to describe and criticize the attributed burden of cancers according to the GBD results by sex and age. METHODS: The GBD 2010 has profited from 100 collaborators worldwide and provides a vast network of data on health outcomes, vital registries, and population surveys. The GBD has used various scientific-approved methods to estimate important health statuses like death rates, life expectancy, and healthy adjusted life expectancy, disability-adjusted life years, years of living lost due to premature death and years of life with disabilities. In the present study, we extracted and graphed the GBD results for Iran in order to present a better scheme for readers. RESULTS: The mortality rate of cancers in Iranians has increased by about 8.5%, the disability-adjusted life year rates have declined by about 9%, and years lost due to premature death have also decreased by about 10% from 1990 to 2010 compared to an 85% increase in years of life with disabilities in the same time period. CONCLUSION: The burden of all non-communicable diseases (NCDs) including cancers showed decrease during the past two decades. However, these diseases still remain worldwide health challenge. Prevention should be considered as an important priority and responsibility. The health authorities also need to determine the burden of cancers at the national and sub-national levels for implementation of effective preventive strategies.