Urokinase-type plasminogen activator and macrophages are required for skeletal muscle hypertrophy in mice.
Adult skeletal muscle possesses remarkable potential for growth in response to mechanical loading; however, many of the cellular and molecular mechanisms involved remain undefined. The hypothesis of this study was that the extracellular serine protease, urokinase-type plasminogen activator (uPA), is required for muscle hypertrophy, in part by promoting macrophage accumulation in muscle subjected to increased mechanical loading. Compensatory muscle hypertrophy was induced in mouse plantaris (PLT) muscles by surgical ablation of synergist muscles. Following synergist ablation, PLT muscles in wild-type mice demonstrated edema and infiltration of neutrophils and macrophages but an absence of overt muscle fiber damage. Sham procedures resulted in no edema or accumulation of inflammatory cells. In addition, synergist ablation was associated with a large increase in activity of uPA in the PLT muscle. uPA-null mice demonstrated complete abrogation of compensatory hypertrophy associated with reduced macrophage accumulation, indicating that uPA is required for hypertrophy. Macrophages isolated from wild-type PLT muscle during compensatory hypertrophy expressed uPA and IGF-I, both of which may contribute to hypertrophy. To determine whether macrophages are required for muscle hypertrophy, clodronate liposomes were administered to deplete macrophages in wild-type mice; this resulted in reduced muscle hypertrophy. Decreased macrophage accumulation was associated with reduced cell proliferation but did not alter signaling through the mammalian target of rapamycin pathway. These data indicate that uPA and macrophages are required for muscle hypertrophy following synergist ablation.
DiPasquale
Dana M
DM
Department of Movement Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA.
Cheng
Ming
M
Billich
William
W
Huang
Sharon A
SA
van Rooijen
Nico
N
Hornberger
Troy A
TA
Koh
Timothy J
TJ
D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology; D004487:Edema / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015870:Gene Expression / Q000187:drug effects; D006984:Hypertrophy; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000032:analysis / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000502:physiology*
D009124:Muscle Proteins; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; C519530:insulin-like growth factor-1, mouse; D004002:Clodronic Acid; D007334:Insulin-Like Growth Factor I; D011494:Protein Kinases; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D014568:Urokinase-Type Plasminogen Activator