Multiple effects of high mobility group box protein 1 in skeletal muscle regeneration.
OBJECTIVE
High mobility group box 1 protein (HMGB1) is a cytokine released by necrotic and inflammatory cells in response to injury. We examined the role of HMGB1 in skeletal muscle regeneration after hindlimb ischemia.


RESULTS
Unilateral hindlimb ischemia was induced in mice by femoral artery dissection. HMGB1 levels increased in regenerating skeletal muscle and the blockade of endogenous HMGB1 by the administration of its truncated form, the BoxA, resulted in the reduction of vessel density. In contrast, intramuscular administration of HMGB1 enhanced perfusion and increased the number of regenerating fibers. To separately study the myogenic and the angiogenic effects of HMGB1, in vitro experiments were performed with isolated myoblasts and endothelial cells. Myoblasts were found to express the HMGB1 receptor RAGE and TLR4 which were downregulated during in vitro myogenic differentiation. HMGB1 was extracellularly released by differentiated myoblasts and exerted a chemotactic activity on myogenic cells. This effect was partially dependent on RAGE and was inhibited by BoxA treatment. Finally, HMGB1 stimulated tubular-like structure formation by endothelial cells through the activation of extracellular signal-regulated kinase (ERK) and JNK signal transduction pathways.


CONCLUSIONS
HMGB1 plays a role in skeletal muscle regeneration modulating, in an autocrine-paracrine manner, myoblast and endothelial cell functions.
De Mori
Roberta
R
Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
Straino
Stefania
S
Di Carlo
Anna
A
Mangoni
Antonella
A
Pompilio
Giulio
G
Palumbo
Roberta
R
Bianchi
Marco E
ME
Capogrossi
Maurizio C
MC
Germani
Antonia
A
D000818:Animals; D019898:Autocrine Communication; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000293:injuries / Q000502:physiology*; D024243:HMGB1 Protein / Q000378:metabolism*; D007511:Ischemia / Q000503:physiopathology*; D051379:Mice; D018482:Muscle, Skeletal / Q000502:physiology*; D032448:Myoblasts, Skeletal / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology; D019899:Paracrine Communication; D012038:Regeneration / Q000502:physiology*
D024243:HMGB1 Protein