Myoferlin is required for insulin-like growth factor response and muscle growth.
Insulin-like growth factor (IGF) is a potent stimulus of muscle growth. Myoferlin is a membrane-associated protein important for muscle development and regeneration. Myoferlin-null mice have smaller muscles and defective myoblast fusion. To understand the mechanism by which myoferlin loss retards muscle growth, we found that myoferlin-null muscle does not respond to IGF1. In vivo after IGF1 infusion, control muscle increased myofiber diameter by 25%, but myoferlin-null muscle was unresponsive. Myoblasts cultured from myoferlin-null muscle and treated with IGF1 also failed to show the expected increase in fusion to multinucleate myotubes. The IGF1 receptor colocalized with myoferlin at sites of myoblast fusion. The lack of IGF1 responsiveness in myoferlin-null myoblasts was linked directly to IGF1 receptor mistrafficking as well as decreased IGF1 signaling. In myoferlin-null myoblasts, the IGF1 receptor accumulated into large vesicular structures. These vesicles colocalized with a marker of late endosomes/lysosomes, LAMP2, specifying redirection from a recycling to a degradative pathway. Furthermore, ultrastructural analysis showed a marked increase in vacuoles in myoferlin-null muscle. These data demonstrate that IGF1 receptor recycling is required for normal myogenesis and that myoferlin is a critical mediator of postnatal muscle growth mediated by IGF1.-Demonbreun, A. R., Posey, A. D., Heretis, K., Swaggart, K. A., Earley, J. U., Pytel, P., McNally, E. M. Myoferlin is required for insulin-like growth factor response and muscle growth.
Demonbreun
Alexis R
AR
Committee on Developmental Biology, The University of Chicago, Chicago, Illinois, USA.
Posey
Avery D
AD
Heretis
Konstantina
K
Swaggart
Kayleigh A
KA
Earley
Judy U
JU
Pytel
Peter
P
McNally
Elizabeth M
EM
D000818:Animals; D002478:Cells, Cultured; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D024510:Muscle Development / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000378:metabolism; D009210:Myofibrils / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D052119:Lysosomal-Associated Membrane Protein 2; D008565:Membrane Proteins; D009124:Muscle Proteins; C519530:insulin-like growth factor-1, mouse; C521810:myoferlin protein, mouse; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1