Impact of fasting on the rhythmic expression of myogenic and metabolic factors in skeletal muscle of adult mice.

Circadian rhythms and metabolism are tightly integrated, and rhythmic expression of metabolic factors is common in homeostatic processes. We measured the temporal changes in the expression of myogenic regulatory factors and expression and activity level of molecules involved in protein metabolism in skeletal muscles and livers in mice and examined the impact of fasting. Tissues were collected over 24 h (at zeitgeber times ZT1, ZT5, ZT9, ZT13, ZT17, ZT21, and ZT1 the following day) from adult male C57Bl/6J mice that had been either freely fed or fasted for 24 h. In skeletal muscle, there was a robust rise in the mRNA expression of the myogenic regulatory factors MyoD and myogenin during dark hours which was strongly suppressed by fasting. Circadian pattern was observed for mRNA of MuRF1, Akt1, and ribosomal protein S6 in muscles in fed and fasted mice and for Fbxo32 in fed mice. Activity (phosphorylation) levels of Akt(Ser473) displayed temporal regulation in fasted (but not fed) mice and were high at ZT9. Fasting caused significant reductions in phosphorylation for both Akt and S6 in muscles, indicative of inactivation. Hepatic phosphorylated Akt(Ser473) and S6(Ser235/236) proteins did not exhibit daily rhythms. Fasting significantly reduced hepatic Akt(473) phosphorylation compared with fed levels, although (unlike in muscle) it did not affect S6(Ser235/236) phosphorylation. This in vivo circadian study addresses for the first time the signaling activities of key molecules related to protein turnover and their possible cross-regulation of expression of genes related to protein degradation.

Is late stent thrombosis in drug-eluting stents a real clinical issue? A single-center experience and review of the literature.

BACKGROUND: Randomized studies have not found an increased rate of late stent thrombosis (LAST) in drug-eluting stents (DES) compared with bare metal stents (BMS) but those studies were statistically not powered to show such a difference. At the same time there is an increasing number of reports of LAST in DES patients in the current literature. PATIENTS AND METHODS: We tried to describe the incidence of LAST in an unselected DES and BMS patient population. All patients who underwent stenting in our hospital between October 2003 and March 2006 were included in the study (n=1377). A total of 424 (30.1%) patients were treated with only BMS stents, 520 (37.8%) with paclitaxel-eluting stents (PES), 384 (27.9%) with sirolimus-eluting stents (SES) and 49 (3.6%) with BMS and DES. Long-term follow-up of all patients was used to determine the incidence of LAST as defined by angiographically proven stent thrombosis associated with acute symptoms more than 30 days after stent implantation. Followup was between 1 month and 2 years 7 months (mean 12 months). Patients treated with DES were younger (66+/-11 years) than BMS patients (72+/-10 years; p<0.001) and more often had diabetes (24.2% vs 17.4%; p < 0.001). A previous PCI had been performed in 27.1% of DES patients vs 13.9% of BMS patients (p < 0.001). RESULTS: There were 9 cases of LAST: 2 with SES (at 6 and 11 months after implantation), 6 with PES (at 6, 9 (2x), 10, 16 and 26 months), and one with BMS (at 22 months). All patients with LAST presented with STEMI and without an angina history that suggested restenosis. Two cases were related to complete cessation of antiplatelet therapy, one because of patient non-compliance (SES), one after aspirin was stopped for orthopedic surgery (BMS). Two cases occurred within 1 month of cessation of clopidogrel therapy and while these patients were on aspirin therapy. Five cases occurred on aspirin monotherapy 2, 3, 4, 10 and 20 months, respectively after planned cessation of clopidogrel. None of the cases occurred under dual antiplatelet therapy. All patients underwent primary PCI; none died. CONCLUSION: Angiographically proven LAST occurred in our unselected patient population with an incidence of 0.84% in patients treated with DES and 0.21% in BMS patients within a mean follow-up of 12 months (p = 0.36). LAST may indeed occur in clinically stable patients while on aspirin monotherapy. Since LAST led in all patients to STEMI it seems to be a serious clinical issue that prompts further investigation and discussion of length of dual platelet therapy.