title: AKAP6 inhibition impairs myoblast differentiation and muscle regeneration: Positive loop between AKAP6 and myogenin.
abstract: Skeletal muscle regeneration occurs continuously to repair muscle damage incurred during normal activity and in chronic disease or injury. Herein, we report that A-kinase anchoring protein 6 (AKAP6) is important for skeletal myoblast differentiation and muscle regeneration. Compared with unstimulated skeletal myoblasts that underwent proliferation, differentiated cells show significant stimulation of AKAP6 expression. AKAP6 knockdown with siRNA effectively halts the formation of myotubes and decreases the expression of the differentiation markers myogenin and myosin heavy chain. When shAKAP6-lentivirus is delivered to mice with cardiotoxin (CTX)-induced muscle injury, muscle regeneration is impaired compared with that of mice injected with control shMock-lentivirus. The motor functions of mice infected with shAKAP6-lentivirus (CTX+shAK6) are significantly worse than those of mice infected with shMock-lentivirus (CTX+shMock). Mechanistic analysis showed that AKAP6 promotes myogenin expression through myocyte enhancer factor 2A (MEF2A). Notably, myogenin increases AKAP6 expression as well. The results of chromatin immunoprecipitation and luciferase assays showed that myogenin binds to an E-box site on the AKAP6 promoter. Taken together, our findings demonstrate a novel interplay between AKAP6 and myogenin, and we suggest that AKAP6 is an important regulator of myoblast differentiation, myotube formation, and muscle regeneration.
authors.affiliation: Biomedical Research Institute and IRICT, Seoul National University Hospital, 101 DaeHak-ro, JongRo-gu Seoul, 110-744, Republic of Korea.
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Biomedical Research Institute and IRICT, Seoul National University Hospital, 101 DaeHak-ro, JongRo-gu Seoul, 110-744, Republic of Korea.
authors.forename: Joo-Yun
authors.initials: JY
authors.lastname: Won
authors.affiliation: Biomedical Research Institute and IRICT, Seoul National University Hospital, 101 DaeHak-ro, JongRo-gu Seoul, 110-744, Republic of Korea.
authors.forename: Jimin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Biomedical Research Institute and IRICT, Seoul National University Hospital, 101 DaeHak-ro, JongRo-gu Seoul, 110-744, Republic of Korea.
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.affiliation: Biomedical Research Institute and IRICT, Seoul National University Hospital, 101 DaeHak-ro, JongRo-gu Seoul, 110-744, Republic of Korea.
authors.forename: Su-Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Biomedical Research Institute and IRICT, Seoul National University Hospital, 101 DaeHak-ro, JongRo-gu Seoul, 110-744, Republic of Korea.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine and IRICT, Seoul National University Hospital, 101 DaeHak-ro, JongRo-gu Seoul, 110-744, Republic of Korea.|Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Korea.
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D024510:Muscle Development / Q000235:genetics* / Q000502:physiology; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism*; D018008:Myogenin / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012038:Regeneration / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D054758:A Kinase Anchor Proteins; C093173:AKAP6 protein, human; C544304:Akap6 protein, mouse; D018008:Myogenin