Inactivation of Sirt6 ameliorates muscular dystrophy in mdx mice by releasing suppression of utrophin expression

Angelina M. Georgieva, Xinyue Guo, Marek Bartkuhn, Stefan Günther, Carsten Künne, Christian Smolka, Ann Atzberger, Ulrich Gärtner, Kamel Mamchaoui, Eva Bober, Yonggang Zhou, Xuejun Yuan () and Thomas Braun ()
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Angelina M. Georgieva: Max Planck Institute for Heart and Lung Research
Xinyue Guo: Max Planck Institute for Heart and Lung Research
Marek Bartkuhn: Justus Liebig University
Stefan Günther: Max Planck Institute for Heart and Lung Research
Carsten Künne: Max Planck Institute for Heart and Lung Research
Christian Smolka: Max Planck Institute for Heart and Lung Research
Ann Atzberger: Max Planck Institute for Heart and Lung Research
Ulrich Gärtner: University of Giessen
Kamel Mamchaoui: Centre de Recherche en Myologie
Eva Bober: Max Planck Institute for Heart and Lung Research
Yonggang Zhou: Max Planck Institute for Heart and Lung Research
Xuejun Yuan: Max Planck Institute for Heart and Lung Research
Thomas Braun: Max Planck Institute for Heart and Lung Research

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract The NAD+-dependent SIRT1-7 family of protein deacetylases plays a vital role in various molecular pathways related to stress response, DNA repair, aging and metabolism. Increased activity of individual sirtuins often exerts beneficial effects in pathophysiological conditions whereas reduced activity is usually associated with disease conditions. Here, we demonstrate that SIRT6 deacetylates H3K56ac in myofibers to suppress expression of utrophin, a dystrophin-related protein stabilizing the sarcolemma in absence of dystrophin. Inactivation of Sirt6 in dystrophin-deficient mdx mice reduced damage of myofibers, ameliorated dystrophic muscle pathology, and improved muscle function, leading to attenuated activation of muscle stem cells (MuSCs). ChIP-seq and locus-specific recruitment of SIRT6 using a CRISPR-dCas9/gRNA approach revealed that SIRT6 is critical for removal of H3K56ac at the Downstream utrophin Enhancer (DUE), which is indispensable for utrophin expression. We conclude that epigenetic manipulation of utrophin expression is a promising approach for the treatment of Duchenne Muscular Dystrophy (DMD).

Date: 2022
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DOI: 10.1038/s41467-022-31798-z

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