TY - JOUR
T1 - MYBPC1 mutations impair skeletal muscle function in zebrafish models of arthrogryposis
AU - Ha, Kyungsoo
AU - Buchan, Jillian G.
AU - Alvarado, David M.
AU - Mccall, Kevin
AU - Vydyanath, Anupama
AU - Luther, Pradeep K.
AU - Goldsmith, Matthew I.
AU - Dobbs, Matthew B.
AU - Gurnett, Christina A.
N1 - Funding Information:
This work was supported by grants from Shriners Hospital, and the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital. P.K.L. and A.V. acknowledge the support of funding from the British Heart Foundation (RG/11/ 21/29335) and EC Grant Agreement n. 241577 (BIG-Heart) FP7 Seventh Framework Programme Health. The Zebrafish International Resource Center is supported by grant P40 RR012546 from the NIH-NCRR. We thank Dr Lila Solnica-Krezel and Kelly Monk for reviewing the manuscript and Doug Oppedal for his help maintaining the zebrafish.
PY - 2013/12
Y1 - 2013/12
N2 - Myosin-binding protein C1 (MYBPC1) is an abundant skeletal muscle protein that is expressed predominantly in slow-twitch muscle fibers. Human MYBPC1 mutations are associated with distal arthrogryposis type 1 and lethal congenital contracture syndrome type 4. As MYBPC1 function is incompletely understood, the mechanism by which human mutations result in contractures is unknown. Here, we demonstrate using antisense morpholino knockdown, that mybpc1 is required for embryonic motor activity and survival in a zebrafish model of arthrogryposis. Mybpc1 morphant embryos have severe body curvature, cardiac edema, impaired motor excitation and are delayed in hatching. Myofibril organization is selectively impaired in slow skeletal muscle and sarcomere numbers are greatly reduced in mybpc1 knockdown embryos, although electron microscopy reveals normal sarcomere structure. To evaluate the effects of human distal arthrogryposis mutations, mybpc1 mRNAs containing the corresponding human W236R and Y856H MYBPC1 mutations were injected into embryos. Dominant-negative effects of these mutations were suggested by the resultant mild bent body curvature, decreased motor activity, as well as impaired overall survival compared with overexpression of wild-type RNA. These results demonstrate a critical role for mybpc1 in slow skeletal muscle development and establish zebrafish as a tractable model of human distal arthrogryposis.
AB - Myosin-binding protein C1 (MYBPC1) is an abundant skeletal muscle protein that is expressed predominantly in slow-twitch muscle fibers. Human MYBPC1 mutations are associated with distal arthrogryposis type 1 and lethal congenital contracture syndrome type 4. As MYBPC1 function is incompletely understood, the mechanism by which human mutations result in contractures is unknown. Here, we demonstrate using antisense morpholino knockdown, that mybpc1 is required for embryonic motor activity and survival in a zebrafish model of arthrogryposis. Mybpc1 morphant embryos have severe body curvature, cardiac edema, impaired motor excitation and are delayed in hatching. Myofibril organization is selectively impaired in slow skeletal muscle and sarcomere numbers are greatly reduced in mybpc1 knockdown embryos, although electron microscopy reveals normal sarcomere structure. To evaluate the effects of human distal arthrogryposis mutations, mybpc1 mRNAs containing the corresponding human W236R and Y856H MYBPC1 mutations were injected into embryos. Dominant-negative effects of these mutations were suggested by the resultant mild bent body curvature, decreased motor activity, as well as impaired overall survival compared with overexpression of wild-type RNA. These results demonstrate a critical role for mybpc1 in slow skeletal muscle development and establish zebrafish as a tractable model of human distal arthrogryposis.
UR - http://www.scopus.com/inward/record.url?scp=84888150799&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddt344
DO - 10.1093/hmg/ddt344
M3 - Article
C2 - 23873045
AN - SCOPUS:84888150799
SN - 0964-6906
VL - 22
SP - 4967
EP - 4977
JO - Human molecular genetics
JF - Human molecular genetics
IS - 24
M1 - ddt344
ER -