title: Age-associated repression of type 1 inositol 1, 4, 5-triphosphate receptor impairs muscle regeneration.
abstract: Skeletal muscle mass and power decrease with age, leading to impairment of mobility and metabolism in the elderly. Ca2+signaling is crucial for myoblast differentiation as well as muscle contraction through activation of transcription factors and Ca2+-dependent kinases and phosphatases. Ca2+channels, such as dihydropyridine receptor (DHPR), two-pore channel (TPC) and inositol 1,4,5-triphosphate receptor (ITPR), function to maintain Ca2+homeostasis in myoblasts. Here, we observed a significant decrease in expression of type 1 IP3 receptor (ITPR1), but not types 2 and 3, in aged mice skeletal muscle and isolated myoblasts, compared with those of young mice. ITPR1 knockdown using shRNA-expressing viruses in C2C12 myoblasts and tibialis anterior muscle of mice inhibited myotube formation and muscle regeneration after injury, respectively, a typical phenotype of aged muscle. This aging phenotype was associated with repression of muscle-specific genes and activation of the epidermal growth factor receptor (EGFR)-Ras-extracellular signal-regulated kinase (ERK) pathway. ERK inhibition by U0126 not only induced recovery of myotube formation in old myoblasts but also facilitated muscle regeneration after injury in aged muscle. The conserved decline in ITPR1 expression in aged human skeletal muscle suggests utility as a potential therapeutic target for sarcopenia, which can be treated using ERK inhibition strategies.
authors.affiliation: Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.|College of Biological Science and Biotechnology, Chungnam National University, Daejeon 34134, Republic of Korea.
authors.forename: Jeong Yi
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.|Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
authors.forename: Chae Young
authors.initials: CY
authors.lastname: Hwang
authors.affiliation: Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon 34113, Republic of Korea.
authors.forename: Bora
authors.initials: B
authors.lastname: Lee
authors.affiliation: Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
authors.forename: Seung-Min
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
authors.forename: Young Jae
authors.initials: YJ
authors.lastname: Bahn
authors.affiliation: Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
authors.forename: Kwang-Pyo
authors.initials: KP
authors.lastname: Lee
authors.affiliation: Graduate School of New Drug Discovery & Development, Chungnam National University, Daejeon 34143, Republic of Korea.
authors.forename: Moonkyung
authors.initials: M
authors.lastname: Kang
authors.affiliation: Graduate School of New Drug Discovery & Development, Chungnam National University, Daejeon 34143, Republic of Korea.
authors.forename: Yeon-Soo
authors.initials: YS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 34143, Republic of Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Woo
authors.affiliation: Department of Rehabilitation Medicine, Seoul National University Bundang Hospital, Gyeonggi-do 13620, Republic of Korea.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Lim
authors.affiliation: College of Biological Science and Biotechnology, Chungnam National University, Daejeon 34134, Republic of Korea.
authors.forename: Eunhee
authors.initials: E
authors.lastname: Kim
authors.affiliation: Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon 34113, Republic of Korea.
authors.forename: Ki-Sun
authors.initials: KS
authors.lastname: Kwon
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D024510:Muscle Development / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D032446:Myoblasts / Q000378:metabolism*; D010641:Phenotype; D012038:Regeneration / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D002118:Calcium
keywords: ITPR1; U0126; muscle aging; muscle regeneration; sarcopenia