BAG3 deficiency results in fulminant myopathy and early lethality.
Bcl-2-associated athanogene 3 (BAG3) is a member of a conserved family of cyto-protective proteins that bind to and regulate Hsp70 family molecular chaperones. Here, we show that BAG3 is prominently expressed in striated muscle and colocalizes with Z-disks. Mice with homozygous disruption of the bag3 gene developed normally but deteriorated postnatally with stunted growth evident by 1 to 2 weeks of age and death by 4 weeks. BAG3-deficient animals developed a fulminant myopathy characterized by noninflammatory myofibrillar degeneration with apoptotic features. Knockdown of bag3 expression in cultured C2C12 myoblasts increased apoptosis on induction of differentiation, suggesting a need for bag3 for maintenance of myotube survival and confirming a cell autonomous role for bag3 in muscle. We conclude that although BAG3 is not required for muscle development, this co-chaperone appears to be critically important for maintenance of mature skeletal muscle.
Homma
Sachiko
S
Burnham Institute for Medical Research, La Jolla, CA, USA.
Iwasaki
Masahiro
M
Shelton
G Diane
GD
Engvall
Eva
E
Reed
John C
JC
Takayama
Shinichi
S
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032448:Myoblasts, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding / Q000235:genetics; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C498806:Bag3 protein, mouse; D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins