Age-associated repression of type 1 inositol 1,4,5-triphosphate receptor impairs muscle regeneration

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Title
Age-associated repression of type 1 inositol 1,4,5-triphosphate receptor impairs muscle regeneration
Author(s)
Jeong Yi Choi; Chae Young Hwang; Bora Lee; Seung Min Lee; Yeong Jae Ban; Kwang-Pyo Lee; M Kang; Y S Kim; S H Woo; J Y Lim; E Kim; Ki Sun Kwon
Bibliographic Citation
Aging-Us, vol. 8, no. 9, pp. 2062-2080
Publication Year
2016
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.
Keyword
ITPR1Muscle agingMuscle regenerationSarcopeniaU0126
ISSN
1945-4589
Publisher
Impact Journals Llc
DOI
http://dx.doi.org/10.18632/aging.101039
Type
Article
Appears in Collections:
1. Journal Articles > Journal Articles
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