Mammalian target of rapamycin (mTOR) is a central controller of cell growth. mTOR assembles into two distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTORC2. Here we show that the mTORC1 component raptor is critical for muscle function and prolonged survival. In contrast, muscles lacking the mTORC2 component rictor are indistinguishable from wild-type controls. Raptor-deficient muscles become progressively dystrophic, are impaired in their oxidative capacity, and contain increased glycogen stores, but they express structural components indicative of oxidative muscle fibers. Biochemical analysis indicates that these changes are probably due to loss of activation of direct downstream targets of mTORC1, downregulation of genes involved in mitochondrial biogenesis, including PGC1alpha, and hyperactivation of PKB/Akt. Finally, we show that activation of PKB/Akt does not require mTORC2. Together, these results demonstrate that muscle mTORC1 has an unexpected role in the regulation of the metabolic properties and that its function is essential for life.

Liver stiffness was measured by transient elastography (FibroScan) in 228 consecutive patients with chronic viral hepatitis, with (115) or without cirrhosis (113), to study its correlations with serum transaminases [alanine aminotransferase (ALT)], fibrosis stage and surrogate noninvasive markers of fibrosis (APRI, FORNS, FibroTest and hyaluronic acid). The dynamic profiles of serum transaminases and liver stiffness were compared by multiple testing in 31 patients during a 6-month follow-up. We identified 8.3 and 14 kPa as the fibrosis >/=F2 and cirrhosis cut-offs, respectively: their sensitivities were 85.2%/78.3%; specificities 90.7%/98.2%; positive predictive values 93.9%/97.8%; negative predictive values 78.8%/81.6%; diagnostic accuracies 87.3%/88.2%. FibroScan performed better than the other surrogate markers of fibrosis (P < 0.001). Other than fibrosis, other factors independently associated with liver stiffness were ALT for all patients and chronic hepatitis patients (P < 0.001), and 12-month persistently normal ALT (biochemical remission, P < 0.001) in cirrhotics. In patients with biochemical remission either spontaneous or after antiviral therapy (48 of 228, 21%), liver stiffness was lower than in patients with identical fibrosis stage, but elevated ALT (P < 0.001). The liver stiffness dynamic profiles paralleled those of ALT, increasing 1.3- to 3-fold during ALT flares in 10 patients with hepatitis exacerbations. Liver stiffness remained unchanged in 21 with stable biochemical activity (P = 0.001). In conclusion, transient elastography is a new liver parameter that behaves as a reliable surrogate marker of fibrosis in chronic viral hepatitis patients, provided that its relationship with major changes of biochemical activity is taken into account.

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Using an oligonucleotide hybridization assay, we studied the clinical implication of wild-type hepatitis B virus (HBV) and a HBV mutant that is unable to secrete hepatitis B e antigen (HBeAg) because of a translational defect due to a stop codon in the pre-C region in 106 hepatitis B surface antigen-positive patients with chronic hepatitis B. Wild-type HBV was detected in 31 of42 (73.8%) HBeAg-positive patients, whereas a mixed viral population was present in 10 (23.8%). Significant differences in the severity and outcome of liver disease were not observed in the two groups of patients. However, the emergence of HBeAg-minus HBV in wild-type HBV carriers was associated with an exacerbation of liver disease and was followed by the presence of antibodies against HBeAg (anti-HBe) in serum in 50% of the cases. In 61 of 64 (95.3%) anti-HBe-positive patients, HBeAg-minus HBV was the predominant virus: HBeAg-minus HBV was detected in 42 patients (65.6%), whereas both wild-type and HBeAg-minus HBV were present in 19 (29.7%). HBeAg-minus HBV was associated with a course of hepatitis characterized by flare-ups of liver cell necrosis interspersed with periods of asymptomatic HBV carriage (P < 0.01). These data support the hypothesis that genetic heterogeneity of HBV significantly influences the course and outcome of chronic hepatitis B. Wild-type HBV secreting HBeAg induces immunologic tolerance and causes chronic infection. HBeAg-minus HBV might be unable to induce chronic infection without the helper function of wildtype HBV, but it appears to be more pathogenic. Once chronic infection is established, HBeAg-minus HBV variants may prevail and displace wild-type virus.Hepatitis B e antigen (HBeAg) is a partially degraded nonparticulate form of hepatitis B nucleocapsid protein secreted into the serum during florid hepatitis B virus (HBV) infection (1-3). HBeAg and polypeptides composing the viral nucleocapsid result from translation of a single open reading frame (C gene) containing two start codons, which identify pre-C and C regions (1-3). Initiation of translation from the first codon (pre-C) yields a secretory protein (HBeAg) with a signal peptide cleaved off during maturation (1-3). In carriers of HBV, disappearance of HBeAg and the presence of antibodies against HBeAg (anti-HBe) in serum is associated with clearance of HBV DNA from serum, hepatitis B core antigen from liver, and the resolution of histological activity (4,5). In areas with high or intermediate HBV endemicity, viral replication and liver damage persist in about 10% of anti-HBe-positive carriers (6-12). HBV mutants unable to secrete HBeAg because of translational defects in the pre-C region have been isolated in these patients (13)(14)(15)(16)(17)(18)(19)(20)(21). In the great majority of them (>90%), an unusual HBV strain was characterized with a G -* A mutation at nucleotide 1896, which generates a stop codon in the pre-C sequence (13-21).In our area, an additional mutation (G --A) at position 1899 was consistently associated with the stop codon...