β3‐Integrin mediates satellite cell differentiation in regenerating mouse muscle

Abstract

Skeletal muscle satellite cells can sense various forms of environmental cues and initiate coordinated signaling that activates myogenesis. Although this process involves cellular membrane receptor integrins, the role of integrins in myogenesis is not well defined. Here, we report a regulatory role of β3-integrin, which was previously thought not expressed in muscle, in the initiation of satellite cell differentiation. Undetected in normal muscle, β3-integrin expression in mouse hindlimb muscles is induced dramatically from 1 to 3 d after injury by cardiotoxin. The source of β3-integrin expression is found to be activated satellite cells. Proliferating C2C12 myoblasts also express β3-integrin, which is further up-regulated transiently on differentiation. Knockdown of β3-integrin expression attenuates Rac1 activity, impairs myogenic gene expression, and disrupts focal adhesion formation and actin organization, resulting in impaired myoblast migration and myotube formation. Conversely, overexpression of constitutively active Rac1 rescues myotube formation. In addition, a β3-integrin- neutralizing antibody similarly blocked myotube formation. Comparing with wild-type littermates, myogenic gene expression and muscle regeneration in cardiotoxin-injured β3-integrin-null mice are impaired, as indicated by depressed expression of myogenic markers and morphological disparities. Thus, β3-integrin is a mediator of satellite cell differentiation in regenerating muscle.