Evaluating the therapeutic potential of mTOR inhibitors using mouse genetics.
Huawei Li,Jennifer L Cotton,David A Guertin
Methods in molecular biology (Clifton, N.J.)
821
2012
Show Abstract
Extensive efforts are underway to develop small-molecule inhibitors of the mammalian target of rapamycin (mTOR) kinase. It is hoped that these inhibitors will have widespread clinical impact in oncology because mTOR is a major downstream effector of PI3K signaling, one of the most frequently activated pathways in cancer. In cells, mTOR is the catalytic core subunit of two distinct complexes, mTORC1 and mTORC2, which are defined by unique mTOR-interacting proteins and have unique functions downstream of PI3K. Two classes of mTOR inhibitors are currently being evaluated as cancer therapeutics: rapamycin and its analogs, which partially inhibit mTORC1 and in some cell types mTORC2, and the recently described ATP-competitive inhibitors, which inhibit the kinase activity of both complexes. Although small molecules that selectively target mTORC2 do not yet exist, experiments using mouse genetics suggest that a theoretical mTORC2 inhibitor may have significant therapeutic value. Here, we discuss an approach to model mTOR complex specific inhibitors using mouse genetics and how it can be applied to other gene products involved in oncogenic signaling to which inhibitors do not exist. | 22125076
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Rapid aminoacidemia enhances myofibrillar protein synthesis and anabolic intramuscular signaling responses after resistance exercise.
West, DW; Burd, NA; Coffey, VG; Baker, SK; Burke, LM; Hawley, JA; Moore, DR; Stellingwerff, T; Phillips, SM
The American journal of clinical nutrition
94
795-803
2011
Show Abstract
Ingestion of whey or casein yields divergent patterns of aminoacidemia that influence whole-body and skeletal muscle myofibrillar protein synthesis (MPS) after exercise. Direct comparisons of the effects of contrasting absorption rates exhibited by these proteins are confounded by their differing amino acid contents.Our objective was to determine the effect of divergent aminoacidemia by manipulating ingestion patterns of whey protein alone on MPS and anabolic signaling after resistance exercise.In separate trials, 8 healthy men consumed whey protein either as a single bolus (BOLUS; 25-g dose) or as repeated, small, "pulsed" drinks (PULSE; ten 2.5-g drinks every 20 min) to mimic a more slowly digested protein. MPS and phosphorylation of signaling proteins involved in protein synthesis were measured at rest and after resistance exercise.BOLUS increased blood essential amino acid (EAA) concentrations above those of PULSE (162% compared with 53%, P less than 0.001) 60 min after exercise, whereas PULSE resulted in a smaller but sustained increase in aminoacidemia that remained elevated above BOLUS amounts later (180-220 min after exercise, P less than 0.05). Despite an identical net area under the EAA curve, MPS was elevated to a greater extent after BOLUS than after PULSE early (1-3 h: 95% compared with 42%) and later (3-5 h: 193% compared with 121%) (both P less than 0.05). There were greater changes in the phosphorylation of the Akt-mammalian target of rapamycin pathway after BOLUS than after PULSE.Rapid aminoacidemia in the postexercise period enhances MPS and anabolic signaling to a greater extent than an identical amount of protein fed in small pulses that mimic a more slowly digested protein. A pronounced peak aminoacidemia after exercise enhances protein synthesis. This trial was registered at clinicaltrials.gov as NCT01319513. | 21795443
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