title: Signaling pathways weigh in on decisions to make or break skeletal muscle.
abstract: OBJECTIVE
  Regulation of muscle size is essential for proper development and homeostasis of adult musculature. This regulation is mediated in large part by signal transduction pathways that promote the synthesis or breakdown of skeletal muscle. PI(3)K/Akt, myostatin and NF-kappaB represent three such pathways that will be the focus of this review.
  
  
  RESULTS
  Recent reports solidify the requirement of the PI(3)K/Akt pathway in the regulation of muscle hypertrophy. In response to IGF-1, Akt activates downstream effectors, mTOR and p70S6K to stimulate protein synthesis thereby increasing the cytoplasmic compartment in muscle fibers. Tsc2 was also identified as a novel Akt target, whose phosphorylation and inactivation by Akt may lead to an increase in cell size. The mechanisms by which myostatin functions in muscle wasting was recently explored using in-vitro assays of myogenesis. Myostatin was found to repress myogenesis by inhibiting the synthesis and activity of MyoD. Paradoxically, myostatin expression is itself regulated by MyoD binding to the myostatin promoter. The NF-kappaB transcription factor also functions as a negative regulator of myogenesis by inhibiting MyoD. Chronic activation of NF-kappaB has been associated with muscle wasting, but the mechanisms by which this regulation occurs remain for the most part unknown.
  
  
  CONCLUSIONS
  Recent cell culture and animal studies have provided insight on the mechanisms by which Akt, myostatin, and NF-kappaB signaling pathways regulate muscle size. Clinical intervention to boost Akt signaling or modulate myostatin and NF-kappaB activities may prove useful in diseases associated with chronic muscle wasting.
authors.affiliation: Division of Human Cancer Genetics, The Ohio State University, Columbus, Ohio, USA. guttridge-1@medctr.osu.edu
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
mesh_terms: D000818:Animals; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D009133:Muscular Atrophy / Q000378:metabolism*; D055435:Myostatin; D016328:NF-kappa B / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C525911:MSTN protein, human; D055435:Myostatin; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D013002:Somatomedins; D016212:Transforming Growth Factor beta; D011494:Protein Kinases; C546842:MTOR protein, human; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases