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Age-associated repression of type 1 inositol 1, 4, 5-triphosphate receptor impairs muscle regeneration
Jeong Yi Choi1,2, Chae Young Hwang1,3, Bora Lee1,4
1Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
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.
Insights
Aging reduces skeletal muscle function by decreasing inositol 1,4,5-triphosphate receptor type 1 (ITPR1) expression. Restoring ITPR1 or inhibiting ERK signaling may combat age-related muscle loss and improve mobility.
Area of Science:
- Cellular and Molecular Biology
- Aging Research
- Muscle Physiology
Background:
- Skeletal muscle aging leads to decreased mass and power, impacting elderly mobility and metabolism.
- Calcium (Ca2+) signaling is vital for myoblast differentiation and muscle contraction.
- Key Ca2+ channels (DHPR, TPC, ITPR) maintain Ca2+ homeostasis in myoblasts.
Purpose of the Study:
- Investigate the role of inositol 1,4,5-triphosphate receptor type 1 (ITPR1) in age-related skeletal muscle decline.
- Determine if ITPR1 downregulation contributes to impaired myogenesis and regeneration in aged muscle.
- Explore therapeutic strategies targeting ITPR1 or downstream pathways for sarcopenia.
Main Methods:
- Compared ITPR1 expression in young versus aged mice skeletal muscle and myoblasts.
- Utilized shRNA-expressing viruses to knockdown ITPR1 in myoblasts and aged mouse muscle.
- Administered ERK inhibitor (U0126) to assess its effects on myotube formation and muscle regeneration.
Main Results:
- Aged mice exhibited significantly decreased ITPR1 expression in skeletal muscle and myoblasts.
- ITPR1 knockdown mimicked age-related phenotypes: inhibited myotube formation and impaired muscle regeneration.
- Downregulation of ITPR1 was linked to repressed muscle-specific genes and activated the EGFR-Ras-ERK pathway.
- ERK inhibition with U0126 restored myotube formation in aged myoblasts and improved muscle regeneration in aged mice.
Conclusions:
- Declined ITPR1 expression is a key feature of skeletal muscle aging.
- The EGFR-Ras-ERK pathway is implicated in the ITPR1-mediated aging phenotype.
- ITPR1 represents a potential therapeutic target for sarcopenia, with ERK inhibition offering a promising treatment strategy.
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