Progressive myopathy and defects in the maintenance of myotendinous junctions in mice that lack talin 1 in skeletal muscle.
The development and function of skeletal muscle depend on molecules that connect the muscle fiber cytoskeleton to the extracellular matrix (ECM). beta1 integrins are ECM receptors in skeletal muscle, and mutations that affect the alpha7beta1 integrin cause myopathy in humans. In mice, beta1 integrins control myoblast fusion, the assembly of the muscle fiber cytoskeleton, and the maintenance of myotendinous junctions (MTJs). The effector molecules that mediate beta1 integrin functions in muscle are not known. Previous studies have shown that talin 1 controls the force-dependent assembly of integrin adhesion complexes and regulates the affinity of integrins for ligands. Here we show that talin 1 is essential in skeletal muscle for the maintenance of integrin attachment sites at MTJs. Mice with a skeletal muscle-specific ablation of the talin 1 gene suffer from a progressive myopathy. Surprisingly, myoblast fusion and the assembly of integrin-containing adhesion complexes at costameres and MTJs advance normally in the mutants. However, with progressive ageing, the muscle fiber cytoskeleton detaches from MTJs. Mechanical measurements on isolated muscles show defects in the ability of talin 1-deficient muscle to generate force. Collectively, our findings show that talin 1 is essential for providing mechanical stability to integrin-dependent adhesion complexes at MTJs, which is crucial for optimal force generation by skeletal muscle.
Conti
Francesco J
FJ
The Scripps Research Institute, Department of Cell Biology and Institute of Childhood and Neglected Disease, La Jolla, CA 92037, USA.
Felder
Amanda
A
Monkley
Sue
S
Schwander
Martin
M
Wood
Malcolm R
MR
Lieber
Richard
R
Critchley
David
D
Müller
Ulrich
U
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D005109:Extracellular Matrix / Q000378:metabolism; D007150:Immunohistochemistry; D019012:Integrin beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012508:Sarcolemma / Q000378:metabolism; D016608:Talin / Q000235:genetics* / Q000378:metabolism; D013710:Tendons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure
D019012:Integrin beta1; D016023:Integrins; C518833:TLN2 protein, mouse; D016608:Talin; C496077:Tln1 protein, mouse