Improved muscle healing through enhanced regeneration and reduced fibrosis in myostatin-null mice.
Numerous stimulatory growth factors that can influence muscle regeneration are known. Recently, it has been demonstrated that neutralization of muscle growth inhibitory factors, such as myostatin (Mstn; also known as growth differentiation factor 8, Gdf8), also leads to increased muscle regeneration in mdx mice that are known to have cycles of degeneration. However, the precise mechanism by which Mstn regulates muscle regeneration has not yet been fully determined. To investigate the role of Mstn in adult skeletal muscle regeneration, wild-type and myostatin-null (Mstn-/-) mice were injured with notexin. Forty-eight hours after injury, accelerated migration and enhanced accretion of myogenic cells (MyoD1+) and macrophages (Mac-1+) was observed at the site of regeneration in Mstn-/- muscle as compared with wild-type muscle. Inflammatory cell numbers decreased more rapidly in the Mstn-/- muscle, indicating that the whole process of inflammatory cell response is accelerated in Mstn-/- mice. Consistent with this result, the addition of recombinant Mstn reduced the activation of satellite cells (SCs) and chemotactic movements of both myoblasts and macrophages ex vivo. Examination of regenerated muscle (28 days after injury) also revealed that Mstn-/- mice showed increased expression of decorin mRNA, reduced fibrosis and improved healing as compared with wild-type mice. On the basis of these results, we propose that Mstn negatively regulates muscle regeneration not only by controlling SC activation but also by regulating the migration of myoblasts and macrophages to the site of injury. Thus, antagonists of Mstn could potentially be useful as pharmacological agents for the treatment of disorders of overt degeneration and regeneration.
McCroskery
Seumas
S
Animal Genomics, AgResearch, Private Bag 3123, East Street, Hamilton, New Zealand.
Thomas
Mark
M
Platt
Leanne
L
Hennebry
Alex
A
Nishimura
Takanori
T
McLeay
Lance
L
Sharma
Mridula
M
Kambadur
Ravi
R
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D058575:Decorin; D004546:Elapid Venoms; D016326:Extracellular Matrix Proteins; D005355:Fibrosis / Q000139:chemically induced; D005786:Gene Expression Regulation; D006097:Granulation Tissue / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000187:drug effects / Q000293:injuries* / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism; D055435:Myostatin; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics* / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
C546879:Dcn protein, mouse; D058575:Decorin; D004546:Elapid Venoms; D016326:Extracellular Matrix Proteins; C525912:Mstn protein, mouse; D055435:Myostatin; D011509:Proteoglycans; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C005082:notexin; D017228:Hepatocyte Growth Factor