title: Bit-1 is an essential regulator of myogenic differentiation.
abstract: Muscle differentiation requires a complex signaling cascade that leads to the production of multinucleated myofibers. Genes regulating the intrinsic mitochondrial apoptotic pathway also function in controlling cell differentiation. How such signaling pathways are regulated during differentiation is not fully understood. Bit-1 (also known as PTRH2) mutations in humans cause infantile-onset multisystem disease with muscle weakness. We demonstrate here that Bit-1 controls skeletal myogenesis through a caspase-mediated signaling pathway. Bit-1-null mice exhibit a myopathy with hypotrophic myofibers. Bit-1-null myoblasts prematurely express muscle-specific proteins. Similarly, knockdown of Bit-1 expression in C2C12 myoblasts promotes early differentiation, whereas overexpression delays differentiation. In wild-type mice, Bit-1 levels increase during differentiation. Bit-1-null myoblasts exhibited increased levels of caspase 9 and caspase 3 without increased apoptosis. Bit-1 re-expression partially rescued differentiation. In Bit-1-null muscle, Bcl-2 levels are reduced, suggesting that Bcl-2-mediated inhibition of caspase 9 and caspase 3 is decreased. Bcl-2 re-expression rescued Bit-1-mediated early differentiation in Bit-1-null myoblasts and C2C12 cells with knockdown of Bit-1 expression. These results support an unanticipated yet essential role for Bit-1 in controlling myogenesis through regulation of Bcl-2.
authors.affiliation: John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813 USA.
authors.forename: Genevieve S
authors.initials: GS
authors.lastname: Griffiths
authors.affiliation: Department of Pharmacology, University of Nevada Medical School, Reno, NV 89557 USA.
authors.forename: Jinger
authors.initials: J
authors.lastname: Doe
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813 USA.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Jijiwa
authors.affiliation: Department of Pharmacology, University of Nevada Medical School, Reno, NV 89557 USA.
authors.forename: Pam
authors.initials: P
authors.lastname: Van Ry
authors.affiliation: Department of Pharmacology, University of Nevada Medical School, Reno, NV 89557 USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Cruz
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813 USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: de la Vega
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813 USA.
authors.forename: Joe W
authors.initials: JW
authors.lastname: Ramos
authors.affiliation: Department of Pharmacology, University of Nevada Medical School, Reno, NV 89557 USA.
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Burkin
authors.affiliation: John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813 USA University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813 USA matter@hawaii.edu.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Matter
mesh_terms: D000818:Animals; D017209:Apoptosis; D002265:Carboxylic Ester Hydrolases / Q000172:deficiency / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D055785:Gene Knockdown Techniques; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D032446:Myoblasts / Q000201:enzymology / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D002265:Carboxylic Ester Hydrolases; C527112:Ptrh2 protein, mouse; D053148:Caspase 3
keywords: Bit‐1; Caspase 3; Differentiation; Myogenesis