TY - JOUR
T1 - Requirement of inducible nitric oxide synthase for skeletal muscle regeneration after acute damage
AU - Rigamonti, Elena
AU - Touvier, Thierry
AU - Clementi, Emilio
AU - Manfredi, Angelo A.
AU - Brunelli, Silvia
AU - Rovere-Querini, Patrizia
PY - 2013/2/15
Y1 - 2013/2/15
N2 - Adult skeletal muscle regeneration results from activation, proliferation, and fusion of muscle stem cells, such as myogenic precursor cells. Macrophages are consistently present in regenerating skeletal muscles and participate into the repair process. The signals involved in the cross-talk between various macrophage populations and myogenic precursor cells have been only partially identified. In this study, we show a key role of inducible NO synthase (iNOS), expressed by classically activated macrophages in the healing of skeletal muscle. We found that, after sterile injury, iNOS expression is required for effective regeneration of the tissue, as myogenic precursor cells in the muscle of injured iNOS-/- mice fail to proliferate and differentiate. We also found that iNOS modulates inflammatory cell recruitment: damaged muscles of iNOS-/- animals express significantly higher levels of chemokines such as MIP2, MCP1, MIP-1α, and MCP1, and display more infiltrating neutrophils after injury and a persistence of macrophages at later time points. Finally, we found that iNOS expression in the injured muscle is restricted to infiltrating macrophages. To our knowledge, these data thus provide the first evidence that iNOS expression by infiltrating macrophages contributes to muscle regeneration, revealing a novel mechanism of inflammation-dependent muscle healing.
AB - Adult skeletal muscle regeneration results from activation, proliferation, and fusion of muscle stem cells, such as myogenic precursor cells. Macrophages are consistently present in regenerating skeletal muscles and participate into the repair process. The signals involved in the cross-talk between various macrophage populations and myogenic precursor cells have been only partially identified. In this study, we show a key role of inducible NO synthase (iNOS), expressed by classically activated macrophages in the healing of skeletal muscle. We found that, after sterile injury, iNOS expression is required for effective regeneration of the tissue, as myogenic precursor cells in the muscle of injured iNOS-/- mice fail to proliferate and differentiate. We also found that iNOS modulates inflammatory cell recruitment: damaged muscles of iNOS-/- animals express significantly higher levels of chemokines such as MIP2, MCP1, MIP-1α, and MCP1, and display more infiltrating neutrophils after injury and a persistence of macrophages at later time points. Finally, we found that iNOS expression in the injured muscle is restricted to infiltrating macrophages. To our knowledge, these data thus provide the first evidence that iNOS expression by infiltrating macrophages contributes to muscle regeneration, revealing a novel mechanism of inflammation-dependent muscle healing.
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U2 - 10.4049/jimmunol.1202903
DO - 10.4049/jimmunol.1202903
M3 - Article
C2 - 23335752
AN - SCOPUS:84873533655
VL - 190
SP - 1767
EP - 1777
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 4
ER -