MSTN carries out its actions via down stream signaling of the transcription

Mstn carries out its actions via down stream

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MSTN carries out its actions via down- stream signaling of the transcription factors SMAD2 and SMAD3, which in turn negatively regulate hypertrophy independent of the cat- abolic enzyme muscle ring finger protein-1 (MuRF-1). Early research indicated that atrophic actions of MSTN were attributed to an inhibition of satellite cell activation, thus impairing protein synthetic capacity (473). Moreover, in vitro research showed that MSTN blunted satellite cell proliferation and
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Hypertrophy-Related Responses and Adaptations to Exercise Stress 25 FIGURE 1.12 Belgian Blue, a breed of cattle known to be null for the myostatin gene. © Eric Isselee/Fotolia.com differentiation (857). However, subsequent research has refuted these findings, showing instead that MSTN inhibition increases muscle mass primarily by acting on muscle fibers as opposed to satellite cells, thereby increasing the cytoplasmic volume to DNA (804). The body of evidence appears to suggest that the primary mechanism of MSTN action in the postnatal period is the modulation of myofi- brillar muscle protein synthesis (12), although it may still play a minor role in regulating satellite cell function (286). The negative regulation of muscle protein synthesis is thought to occur via a combined inhibition of the Akt/mTOR pathway (see chapter 2) as well as downregulation of both calcineurin signaling and the transcription factors MyoD and myogenin (784). Myostatin-induced inhi- bition of mTOR is self-perpetuating, because this downregulation in turn further amplifies MSTN signaling (250). In addition to acutely upregulating numer- ous growth-related factors, resistance train- ing also downregulates inhibitory factors including MSTN (366). Untrained people show modest decreases in MSTN following a resistance exercise bout, and these reductions are more than 3-fold greater with consistent resistance training experience (516). However, MSTN does not seem to play a significant role as an inhibitor of exercise-induced hypertro- phy in normal healthy adults expressing a fair amount of muscle MSTN protein and mRNA (366). Therefore, what, if any, effects these changes have on long-term increases in muscle growth remains uncertain (215). Other Myokines A number of additional myokines have been identified, and emerging evidence indicates that many may play a role in hypertrophic adaptations. Perhaps the most intriguing of these is hepatocyte growth factor (HGF), which exerts mitogenic actions on numerous bodily tissues including muscle. Evidence shows that HGF is critical for the activation of dormant
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Science and Development of Muscle Hypertrophy 26 satellite cells (11). To date, HGF is the only myokine shown to stimulate dormant satellite cells to enter the cell cycle early both in vitro and in vivo (748). The active form of HGF is present in the extracellular compartment of uninjured skeletal muscle (746), and it is activated by mechanical signaling via the dystrophin-as- sociated protein complex (11). Muscular contractions alter this complex, leading to nitric oxide synthase activation, which stim-
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