Open AccessSonic hedgehog regulates angiogenesis and myogenesis during post‐natal skeletal muscle regeneration
Author(s) -
Straface Giuseppe,
Aprahamian Tamar,
Flex Andrea,
Gaetani Eleonora,
Biscetti Federico,
Smith Roy C.,
Pecorini Giovanni,
Pola Enrico,
Angelini Flavia,
Stigliano Egidio,
Castellot Jr. John J.,
Losordo Douglas W.,
Pola Roberto
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2008.00440.x
Subject(s) - myogenesis , sonic hedgehog , myod , skeletal muscle , biology , myod protein , smoothened , angiogenesis , hedgehog signaling pathway , morphogen , microbiology and biotechnology , myogenic regulatory factors , regeneration (biology) , endocrinology , medicine , cancer research , signal transduction , genetics , gene
Sonic hedgehog (Shh) is a morphogen‐regulating crucial epithelial‐mesenchymal interactions during embryonic development, but its signalling pathway is considered generally silent in post‐natal life. In this study, we demonstrate that Shh is de novo expressed after injury and during regeneration of the adult skeletal muscle. Shh expression is followed by significant up‐regulation of its receptor and target gene Ptc1 in injured and regenerating muscles. The reactivation of the Shh signalling pathway has an important regulatory role on injury‐induced angiogenesis, as inhibition of Shh function results in impaired up‐regulation of prototypical angiogenic agents, such as vascular endothelial growth factor (VEGF) and stromal‐derived factor (SDF)‐1alpha, decreased muscle blood flow and reduced capillary density after injury. In addition, Shh reactivation plays a regulatory role on myogenesis, as its inhibition impairs the activation of the myogenic regulatory factors Myf‐5 and MyoD, decreases the up‐regulation of insulin‐like growth factor (IGF)‐1 and reduces the number of myogenic satellite cells at injured site. Finally, Shh inhibition results in muscle fibrosis, increased inflammatory reaction and compromised motor functional recovery after injury. These data demonstrate that the Shh pathway is functionally important for adult skeletal muscle regeneration and displays pleiotropic angiogenic and myogenic potentials in post‐natal life. These findings might constitute the foundation for new therapeutic approaches for muscular diseases in humans.