Deacetylase inhibitors increase muscle cell size by promoting myoblast recruitment and fusion through induction of follistatin.
Fusion of undifferentiated myoblasts into multinucleated myotubes is a prerequisite for developmental myogenesis and postnatal muscle growth. We report that deacetylase inhibitors favor the recruitment and fusion of myoblasts into preformed myotubes. Muscle-restricted expression of follistatin is induced by deacetylase inhibitors and mediates myoblast recruitment and fusion into myotubes through a pathway distinct from those utilized by either IGF-1 or IL-4. Blockade of follistatin expression by RNAi-mediated knockdown, functional inactivation with either neutralizing antibodies or the antagonist protein myostatin, render myoblasts refractory to HDAC inhibitors. Muscles from animals treated with the HDAC inhibitor trichostatin A display increased production of follistatin and enhanced expression of markers of regeneration following muscle injury. These data identify follistatin as a central mediator of the fusigenic effects exerted by deacetylase inhibitors on skeletal muscles and establish a rationale for their use to manipulate skeletal myogenesis and promote muscle regeneration.
Iezzi
Simona
S
Muscle Gene Expression Group, Laboratory of Muscle Biology, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
Di Padova
Monica
M
Serra
Carlo
C
Caretti
Giuseppina
G
Simone
Cristiano
C
Maklan
Eric
E
Minetti
Giulia
G
Zhao
Po
P
Hoffman
Eric P
EP
Puri
Pier Lorenzo
PL
Sartorelli
Vittorio
V
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D038681:Follistatin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008561:Membrane Fusion / Q000235:genetics; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology / Q000254:growth & development*; D017570:MyoD Protein / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D050778:NFATC Transcription Factors; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins; D034622:RNA Interference; D012038:Regeneration / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
D000906:Antibodies; C115163:CREB1 protein, human; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D038681:Follistatin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D017570:MyoD Protein; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; C012589:trichostatin A; D006655:Histone Deacetylases