Catalpol counteracts the pathology in a mouse model of Duchenne muscular dystrophy by inhibiting the TGF-β1/TAK1 signaling pathway

Deng-qiu Xu1, Lei Zhao2, Si-jia Li1, Xiao-fei Huang1, Chun-jie Li1, Li-xin Sun1, Xi-hua Li2, Lu-yong Zhang1,3,4, Zhen-zhou Jiang1,4
1 Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
2 Department of Neurology, Children’s Hospital of Fudan University, Shanghai 200032, China
3 Center for Drug Screening and Pharmacodynamics Evaluation, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
4 Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 210009, China
Correspondence to: Lu-yong Zhang:, Zhen-zhou Jiang:,
DOI: 10.1038/s41401-020-00515-1
Received: 11 May 2020
Accepted: 18 August 2020
Advance online: 16 September 2020


Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by a mutation in the gene encoding the dystrophin protein. Catalpol is an iridoid glycoside found in Chinese herbs with anti-inflammatory, anti-oxidant, anti-apoptotic, and hypoglycemic activities that can protect against muscle wasting. In the present study we investigated the effects of catalpol on DMD. Aged Dystrophin-deficient (mdx) mice (12 months old) were treated with catalpol (100, 200 mg·kg−1·d−1, ig) for 6 weeks. At the end of the experiment, the mice were sacrificed, and gastrocnemius (GAS), tibialis anterior (TA), extensor digitorum longus (EDL), soleus (SOL) muscles were collected. We found that catalpol administration dose-dependently increased stride length and decreased stride width in Gait test. Wire grip test showed that the time of wire grip and grip strength were increased. We found that catalpol administration dose-dependently alleviated skeletal muscle damage, evidenced by reduced plasma CK and LDH activity as well as increased the weight of skeletal muscles. Catalpol administration had no effect on dystrophin expression, but exerted anti-inflammatory effects. Furthermore, catalpol administration dose-dependently decreased tibialis anterior (TA) muscle fibrosis, and inhibited the expression of TGF-β1, TAK1 and α-SMA. In primary myoblasts from mdx mice, knockdown of TAK1 abolished the inhibitory effects of catalpol on the expression levels of TGF-β1 and α-SMA. In conclusion, catalpol can restore skeletal muscle strength and alleviate skeletal muscle damage in aged mdx mice, thus may provide a novel therapy for DMD. Catalpol attenuates muscle fibrosis by inhibiting the TGF-β1/TAK1 signaling pathway.
Keywords: Duchenne muscular dystrophy; catalpol; TGF-β1; TAK1; α-SMA; muscle fibrosis

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