Eps 15 Homology Domain (EHD)-1 Remodels Transverse Tubules in Skeletal Muscle.
We previously showed that Eps15 homology domain-containing 1 (EHD1) interacts with ferlin proteins to regulate endocytic recycling. Myoblasts from Ehd1-null mice were found to have defective recycling, myoblast fusion, and consequently smaller muscles. When expressed in C2C12 cells, an ATPase dead-EHD1 was found to interfere with BIN1/amphiphysin 2. We now extended those findings by examining Ehd1-heterozygous mice since these mice survive to maturity in normal Mendelian numbers and provide a ready source of mature muscle. We found that heterozygosity of EHD1 was sufficient to produce ectopic and excessive T-tubules, including large intracellular aggregates that contained BIN1. The disorganized T-tubule structures in Ehd1-heterozygous muscle were accompanied by marked elevation of the T-tubule-associated protein DHPR and reduction of the triad linker protein junctophilin 2, reflecting defective triads. Consistent with this, Ehd1-heterozygous muscle had reduced force production. Introduction of ATPase dead-EHD1 into mature muscle fibers was sufficient to induce ectopic T-tubule formation, seen as large BIN1 positive structures throughout the muscle. Ehd1-heterozygous mice were found to have strikingly elevated serum creatine kinase and smaller myofibers, but did not display findings of muscular dystrophy. These data indicate that EHD1 regulates the maintenance of T-tubules through its interaction with BIN1 and links T-tubules defects with elevated creatine kinase and myopathy.
Center for Genetic Medicine, Northwestern University, Chicago, IL, United States of America.
Alexis R
AR
Demonbreun
Department of Pathology, The University of Chicago, Chicago, IL, United States of America.
Kaitlin E
KE
Swanson
Department of Medicine, The University of Chicago, Chicago, IL, United States of America.
Ann E
AE
Rossi
Department of Medicine, The University of Chicago, Chicago, IL, United States of America.
H Kieran
HK
Deveaux
Center for Genetic Medicine, Northwestern University, Chicago, IL, United States of America.
Judy U
JU
Earley
Center for Genetic Medicine, Northwestern University, Chicago, IL, United States of America.
Madison V
MV
Allen
Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE, United States of America.
Priyanka
P
Arya
Department of Pathology & Microbiology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, United States of America.
Sohinee
S
Bhattacharyya
Department of Pathology & Microbiology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, United States of America.
Hamid
H
Band
Department of Pathology, The University of Chicago, Chicago, IL, United States of America.
Peter
P
Pytel
Center for Genetic Medicine, Northwestern University, Chicago, IL, United States of America.
Elizabeth M
EM
McNally
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D003402:Creatine Kinase / Q000378:metabolism; D006579:Heterozygote; D008297:Male; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D018482:Muscle, Skeletal / Q000502:physiology*; D009135:Muscular Diseases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology; D033921:Vesicular Transport Proteins / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C109221:Bin1 protein, mouse; C485640:Ehd1 protein, mouse; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D033921:Vesicular Transport Proteins; D003402:Creatine Kinase