2. Academic Validation
  3. Oxidative stress-induced premature senescence and aggravated denervated skeletal muscular atrophy by regulating progerin-p53 interaction

Oxidative stress-induced premature senescence and aggravated denervated skeletal muscular atrophy by regulating progerin-p53 interaction

  • Skelet Muscle. 2022 Jul 29;12(1):19. doi: 10.1186/s13395-022-00302-y.
Yaoxian Xiang  # 1 2 3,  Zongqi You  # 1 2 3,  Xinying Huang  # 1 2 3 4,  Junxi Dai 1 2 3,  Junpeng Zhang 5,  Shuqi Nie 4,  Lei Xu 1 2 3,  Junjian Jiang 6 7 8,  Jianguang Xu 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
  • 2 NHC Key Laboratory of Hand Reconstruction, (Fudan University), Shanghai, People's Republic of China.
  • 3 Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai, People's Republic of China.
  • 4 Shanghai Medical College of Fudan University, Shanghai, People's Republic of China.
  • 5 School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China.
  • 6 Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China. jjjdoctor@126.com.
  • 7 NHC Key Laboratory of Hand Reconstruction, (Fudan University), Shanghai, People's Republic of China. jjjdoctor@126.com.
  • 8 Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai, People's Republic of China. jjjdoctor@126.com.
  • 9 Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai, People's Republic of China. xjg@shutcm.edu.cn.
  • 10 NHC Key Laboratory of Hand Reconstruction, (Fudan University), Shanghai, People's Republic of China. xjg@shutcm.edu.cn.
  • 11 Shanghai Key Laboratory of Peripheral Nerve and Microsurgery, Shanghai, People's Republic of China. xjg@shutcm.edu.cn.
  • 12 School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China. xjg@shutcm.edu.cn.
  • # Contributed equally.
PMID: 35906707 DOI: 10.1186/s13395-022-00302-y
Abstract

Background: Progerin elevates atrophic gene expression and helps modify the nuclear membrane to cause severe muscle pathology, which is similar to muscle weakness in the elderly, to alter the development and function of the skeletal muscles. Stress-induced premature senescence (SIPS), a state of cell growth arrest owing to such stimuli as oxidation, can be caused by progerin. However, evidence for whether SIPS-induced progerin accumulation is connected to denervation-induced muscle atrophy is not sufficient.

Methods: Flow cytometry and a Reactive Oxygen Species (ROS) as well as inducible nitric oxide synthase (iNOS) inhibitors were used to assess the effect of oxidation on protein (p53), progerin, and nuclear progerin-p53 interaction in the denervated muscles of models of mice suffering from sciatic injury. Loss-of-function approach with the targeted deletion of p53 was used to assess connection among SIPS, denervated muscle atrophy, and fibrogenesis.

Results: The augmentation of ROS and iNOS-derived NO in the denervated muscles of models of mice suffering from sciatic injury upregulates p53 and progerin. The abnormal accumulation of progerin in the nuclear membrane as well as the activation of nuclear progerin-p53 interaction triggered premature senescence in the denervated muscle cells of mice. The p53-dependent SIPS in denervated muscles contributes to their atrophy and fibrogenesis.

Conclusion: Oxidative stress-triggered premature senescence via nuclear progerin-p53 interaction that promotes denervated skeletal muscular atrophy and fibrogenesis.

Keywords

Denervated muscle atrophy; NO; P53; Progerin; ROS.

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