BackgroundSirtuin 3 (SIRT3) is one of the seven mammalian sirtuins, which are homologs of the yeast Sir2 gene. SIRT3 is the only sirtuin with a reported association with the human life span. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) plays important roles in adaptive thermogenesis, gluconeogenesis, mitochondrial biogenesis and respiration. PGC-1α induces several key reactive oxygen species (ROS)-detoxifying enzymes, but the molecular mechanism underlying this is not well understood.ResultsHere we show that PGC-1α strongly stimulated mouse Sirt3 gene expression in muscle cells and hepatocytes. Knockdown of PGC-1α led to decreased Sirt3 gene expression. PGC-1α activated the mouse SIRT3 promoter, which was mediated by an estrogen-related receptor (ERR) binding element (ERRE) (−407/−399) mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that ERRα bound to the identified ERRE and PGC-1α co-localized with ERRα in the mSirt3 promoter. Knockdown of ERRα reduced the induction of Sirt3 by PGC-1α in C2C12 myotubes. Furthermore, Sirt3 was essential for PGC-1α-dependent induction of ROS-detoxifying enzymes and several components of the respiratory chain, including glutathione peroxidase-1, superoxide dismutase 2, ATP synthase 5c, and cytochrome c. Overexpression of SIRT3 or PGC-1α in C2C12 myotubes decreased basal ROS level. In contrast, knockdown of mSIRT3 increased basal ROS level and blocked the inhibitory effect of PGC-1α on cellular ROS production. Finally, SIRT3 stimulated mitochondrial biogenesis, and SIRT3 knockdown decreased the stimulatory effect of PGC-1α on mitochondrial biogenesis in C2C12 myotubes.ConclusionOur results indicate that Sirt3 functions as a downstream target gene of PGC-1α and mediates the PGC-1α effects on cellular ROS production and mitochondrial biogenesis. Thus, SIRT3 integrates cellular energy metabolism and ROS generation. The elucidation of the molecular mechanisms of SIRT3 regulation and its physiological functions may provide a novel target for treating ROS-related disease.

Background Systematic data on discontinuation of statins in routine practice of medicine are limited. Objective To investigate reasons for statin discontinuation and the role of statin-related events (clinical events / symptoms thought to have been caused by statins) in routine care settings. Design A retrospective cohort study Setting Practices affiliated with one of two academic hospitals. Patients Adults who received a statin prescription between 01/01/2000 and 12/31/2008. Measurements Information on reasons for statin discontinuations was obtained from a combination of structured electronic medical record (EMR) entries and analysis of electronic provider notes by validated software. Results Statins were discontinued at least temporarily for 57,292 out of 107,835 patients. Statin-related events were documented for 18,778 (17.4%) patients. Statins were discontinued at least temporarily by 11,124 of these patients, 6,579 (59.1%) of whom were rechallenged with a statin over the subsequent 12 months. Most patients who were rechallenged (92.2%) were still taking a statin 12 months after the statin-related event. Among the 2,721 patients who were rechallenged with the same statin to which they had a statin-related event, 1,295 (47.6%) were on the same statin 12 months later, including 996 on the same or higher dose. Limitation Statin discontinuations and statin-related events were assessed in practices affiliated with two academic medical centers. Utilization of secondary data could have led to missing or misinterpreted data as a result of incomplete documentation. Natural language processing tools used to compensate for the low (30%) proportion of reasons for statin discontinuation documented in structured EMR fields are not perfectly accurate. Conclusion Statin-related events are commonly reported and often lead to their discontinuation. However, most patients who are rechallenged can tolerate statins long-term. This suggests that many of the statin-related events may have other etiologies, are tolerable or may be specific to individual statins rather than the entire drug class.

Tumor-induced osteomalacia (TIO) is an acquired form of hypophosphatemia. Tumor resection leads to cure. We investigated the clinical characteristics of TIO, diagnostic methods, and course after tumor resection in Beijing, China, and compared them with 269 previous published reports of TIO. A total of 94 patients with adult-onset hypophosphatemic osteomalacia were seen over a 6-year period (January, 2004 to May, 2010 in Peking Union Medical College Hospital. After physical examination (PE), all patients underwent technetium-99m octreotide scintigraphy ( 99 Tc m -OCT). Tumors were removed after localization. The results demonstrated that 46 of 94 hypophosphatemic osteomalacia patients had high uptake in 99 Tc m -OCT imaging. Forty of them underwent tumor resection with the TIO diagnosis established in 37 patients. In 2 patients, the tumor was discovered on PE but not by 99 Tc m -OCT. The gender distribution was equal (M/F ¼ 19/20). Average age was 42 AE 14 years. In 35 patients (90%), the serum phosphorus concentration returned to normal in 5.5 AE 3.0 days after tumor resection. Most of the tumors (85%) were classified as phosphaturic mesenchymal tumor (PMT) or mixed connective tissue variant (PMTMCT). Recurrence of disease was suggested in 3 patients (9%). When combined with the 269 cases reported in the literature, the mean age and sex distribution were similar. The tumors were of bone (40%) and soft tissue (55%) origins, with 42% of the tumors being found in the lower extremities. In summary, TIO is an important cause of adult-onset hypophosphatemia in China. 99 Tc m -OCT imaging successfully localized the tumor in the overwhelming majority of patients. Successful removal of tumors leads to cure in most cases, but recurrence should be sought by long-term follow-up. ß