1. Academic Validation
  2. PGC-1α participates in regulating mitochondrial function in aged sarcopenia through effects on the Sestrin2-mediated mTORC1 pathway

PGC-1α participates in regulating mitochondrial function in aged sarcopenia through effects on the Sestrin2-mediated mTORC1 pathway

  • Exp Gerontol. 2024 Jun 1:190:112428. doi: 10.1016/j.exger.2024.112428.
Yimin Fu 1 Lei Tao 2 Xiaojun Wang 1 Binyou Wang 3 Weilin Qin 4 Lei Song 5
Affiliations

Affiliations

  • 1 Geriatric Medicine Department, Yantai Yuhuangding Hospital, Yantai 264000, China.
  • 2 Department of Rheumatology&Immunology, the Second Affiliated Hospital of Shandong First Medical University, Tai'an 271000, China.
  • 3 Department of Geriatrics, Second People's Hospital of Chengdu, Chengdu 610000, China.
  • 4 Department of Geriatrics, Qinghai Provincial People's Hospital, Xi'ning 810001, China. Electronic address: 330854773@qq.com.
  • 5 Geriatric Medicine Department, Yantai Yuhuangding Hospital, Yantai 264000, China. Electronic address: song990125@163.com.
Abstract

Background: Mitochondrial dysregulation in skeletal myocytes is considered a major factor in aged sarcopenia. In this study, we aimed to study the effects of Peroxisome Proliferator-activated Receptor gamma coactivator-1 alpha (PGC-1α) on Sestrin2-mediated mechanistic target of rapamycin complex 1 (mTORC1) in aged skeletal muscles.

Methods: C2C12 myoblasts were stimulated by 50 μM 7β-hydroxycholesterol (7β-OHC) to observe the changes of DNA damage, mitochondrial membrane potential (Δψm), mitochondrial ROS and PGC-1α protein. The PGC-1α silence in the C2C12 cells was established by siRNA transfection. The levels of DNA damage, Δψm, mitochondrial ROS, Sestrin2 and p-S6K1/S6K1 proteins were observed after the PGC-1α silence in the C2C12 cells. Recombinant Sestrin2 treatment was used to observe the changes of DNA damage, Δψm, mitochondrial ROS and p-S6K1/S6K1 protein in the 7β-OHC-treated or PGC-1α siRNA-transfected C2C12 cells. Wild-type (WT) mice and muscle-specific PGC-1α conditional knockout (MKO) mice, including young and old, were used to analyse the effects of PGC-1α on muscle function and the levels of Sestrin2 and p-S6K1 in the white gastrocnemius muscles. Recombinant Sestrin2 was administrated to analyse its effects on muscle function in the old WT mice and old MKO mice.

Results: 7β-OHC treatment induced DNA damage, mitochondrial dysfunction and decrease of PGC-1α protein in the C2C12 cells. PGC-1α silence also induced DNA damage and mitochondrial dysfunction in the C2C12 cells. Additionally, PGC-1α silence or 7β-OHC treatment decreased the levels of Sestrin2 and p-S6K1/S6K1 protein in the C2C12 cells. Recombinant Sestrin2 treatment significantly improved the DNA damage and mitochondrial dysfunction in the 7β-OHC-treated or PGC-1α siRNA-transfected C2C12 cells. At the same age, muscle-specific PGC-1α deficiency aggravated aged sarcopenia and decreased the levels of Sestrin2 and p-S6K1 in the white gastrocnemius muscles when compared to the WT mice. Recombinant Sestrin2 treatment improved muscle function and increased p-S6K1 levels in the old two genotypes.

Conclusion: This research demonstrates that PGC-1α participates in regulating mitochondrial function in aged sarcopenia through effects on the Sestrin2-mediated mTORC1 pathway.

Keywords

7β-hydroxycholesterol; Mitochondrial dysregulation; Muscle function; PGC-1α conditional knockout.

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