PTEN Inhibition Ameliorates Muscle Degeneration and Improves Muscle Function in a Mouse Model of Duchenne Muscular Dystrophy

• Published in: Molecular therapy 2021-01, Vol.29 (1), p.132-148
• Main Authors: Yue, Feng, Song, Changyou, Huang, Di, Narayanan, Naagarajan, Qiu, Jiamin, Jia, Zhihao, Yuan, Zhengrong, Oprescu, Stephanie N., Roseguini, Bruno T., Deng, Meng, Kuang, Shihuan
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers; Disease Models, Animal; Gene Knockdown Techniques; Lipid Metabolism; Mice; Mice, Inbred mdx; muscle wasting; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscle, Skeletal - ultrastructure; Muscular Dystrophy, Duchenne - genetics; Muscular Dystrophy, Duchenne - physiopathology; myofiber membrane integrity; Original; PTEN Phosphohydrolase - genetics; Regeneration - genetics; VO-OHpic
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2020.09.029

Duchenne muscular dystrophy (DMD) is caused by a mutation of the muscle membrane protein dystrophin and characterized by severe degeneration of myofibers, progressive muscle wasting, loss of mobility, and, ultimately, cardiorespiratory failure and premature death. Currently there is no cure for DMD. Herein, we report that skeletal muscle-specific knockout (KO) of the phosphatase and tensin homolog (Pten) gene in an animal model of DMD (mdx mice) alleviates myofiber degeneration and restores muscle function without increasing tumor incidence. Specifically, Pten KO normalizes myofiber size and prevents muscular atrophy, and it improves grip strength and exercise performance in mdx mice. Pten KO also reduces fibrosis and inflammation, and it ameliorates muscle pathology in mdx mice. Unbiased RNA sequencing reveals that Pten KO upregulates extracellular matrix and basement membrane components positively correlated with wound healing and suppresses negative regulators of wound healing and lipid biosynthesis, thus improving the integrity of muscle basement membrane at the ultrastructural level. Importantly, pharmacological inhibition of PTEN similarly ameliorates muscle pathology and improves muscle integrity and function in mdx mice. Our findings provide evidence that PTEN inhibition may represent a potential therapeutic strategy to restore muscle function in DMD. [Display omitted] Phosphatase and tensin homolog (PTEN) is a tumor suppressor and negative regulator of muscle growth. Yue et al. now show that inhibition of PTEN by genetic knockout of the gene or a pharmacological inhibitor improves muscle function and ameliorates muscle pathology in a mouse model of Duchenne muscular dystrophy.