Kindlin-2 is required for myocyte elongation and is essential for myogenesis

James J Dowling,Susie Kim,Eva L Feldman,Jeffrey Golden,Andrew P Vreede

doi:10.1186/1471-2121-9-36

James J Dowling, Susie Kim + Show 3 more

Open Access

https://doi.org/10.1186/1471-2121-9-36

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Abstract

BackgroundIntegrins are required for normal muscle differentiation and disruptions in integrin signaling result in human muscle disease. The intracellular components that regulate integrin function during myogenesis are poorly understood. Unc-112 is an integrin-associated protein required for muscle development in C. elegans. To better understand the intracellular effectors of integrin signaling in muscle, we examined the mammalian homolog of Unc-112, kindlin-2.ResultsKindlin-2 expression is upregulated during differentiation and highly enriched at sites of integrin localization. RNAi knockdown of kindlin-2 in C2C12 cells results in significant abnormalities during the early stages of myogenesis. Specifically, differentiating myocytes lacking kindlin-2 are unable to elongate and fail to fuse into multinucleated myotubes. These changes are correlated with decreased cell substratum adhesion and increased cell motility. They are also associated with redistribution of a known kindlin-2 binding partner, integrin linked kinase (ILK), to the membrane insoluble subcellular fraction.ConclusionIn all, our study reveals kindlin-2 as a novel integrin adaptor protein important for muscle differentiation, and identifies it particularly as a critical regulator of myocyte elongation.

Highlights

Integrins are required for normal muscle differentiation and disruptions in integrin signaling result in human muscle disease
Our study reveals that the integrin associated cytoplasmic effector molecule kindlin2 is a critical regulator of myogenesis, and implicates kindlin-2 and integrin junctions in the regulation of myocyte elongation
Kindlin-2 is enriched during early myogenesis To study the expression and function of kindlin-2 during myogenesis, we utilized the well-characterized C2C12 cell culture model system

Summary

Introduction

Integrins are required for normal muscle differentiation and disruptions in integrin signaling result in human muscle disease. The intracellular components that regulate integrin function during myogenesis are poorly understood. Unc-112 is an integrin-associated protein required for muscle development in C. elegans. To better understand the intracellular effectors of integrin signaling in muscle, we examined the mammalian homolog of Unc-112, kindlin-2. The formation of myotubes from mononucleated precursor myoblasts via myogenesis is a complex, highly regulated process requiring both genetic and morphologic changes[1,2]. Understanding the molecular components of myogenesis is of high biologic and clinical importance, as the differentiation program is employed during development and in the muscle regeneration response to injury[3]. Integrins are implicated in many other aspects of myogenesis, especially those related to the morphologic changes that accompany the differentia-

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