Muscle‐specific sirtuin1 gain‐of‐function ameliorates skeletal muscle atrophy in a pre‐clinical mouse model of cerebral ischemic stroke

• Main Authors: Kiril Tuntevski, Ameena Hajira, Austin Nichols, Stephen E. Alway, Junaith S. Mohamed
• Format: Article
• Language: English
• Published: Wiley 2020-07-01
• Series: FASEB BioAdvances
• Subjects: cerebral ischemic stroke; muscle atrophy; PARP‐1; SirT1; ZNF216
• Online Access: https://doi.org/10.1096/fba.2020-00017

Abstract Stroke causes severe long‐term disability in patients due to the induction of skeletal muscle atrophy and weakness, but the molecular mechanisms remain elusive. Using a preclinical mouse model of cerebral ischemic stroke, we show that stroke robustly induced atrophy and significantly decreased SirT1 gene expression in the PTA (paralytic tibialis anterior) muscle. Muscle‐specific SirT1 gain‐of‐function mice are resistant to stroke‐induced muscle atrophy and this protective effect requires its deacetylase activity. Although SirT1 counteracts the stroke‐induced up‐regulation of atrogin1, MuRF1 and ZNF216 genes, we found a mechanism that regulates the ZNF216 gene transcription in post‐stroke muscle. Stroke increased the expression of the ZNF216 gene in PTA muscle by activating PARP‐1, which binds on the ZNF216 promoter. The SirT1 gain‐of‐function or SirT1 activator, resveratrol, reversed the PARP‐1‐mediated up‐regulation of ZNF216 expression at the promoter level, suggesting a contradicted role for SirT1 and PARP‐1 in the regulation of ZNF216 gene. Overall, our study for the first‐time demonstrated that (a) stroke causes muscle atrophy, in part, through the SirT1/PARP‐1/ZNF216 signaling mechanism; (b) SirT1 can block muscle atrophy in response to different types of atrophic signals via different signaling mechanisms; and (c) SirT1 is a critical regulator of post‐stroke muscle mass.