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Emerging evidence implicates RhoA\/Rho\u2010associated protein kinase (ROCK) signalling in DMD pathology, yet its direct role in DMD muscle function, and related mechanisms, are unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Three\u2010dimensionally engineered dystrophin\u2010deficient <jats:italic>mdx<\/jats:italic> skeletal muscles and <jats:italic>mdx<\/jats:italic> mice were used to test the role of ROCK in DMD muscle function <jats:italic>in vitro<\/jats:italic> and <jats:italic>in situ<\/jats:italic>, respectively. The role of ARHGEF3, one of the RhoA guanine nucleotide exchange factors (GEFs), in RhoA\/ROCK signalling and DMD pathology was examined by generating <jats:italic>Arhgef3<\/jats:italic> knockout <jats:italic>mdx<\/jats:italic> mice. The role of RhoA\/ROCK signalling in mediating the function of ARHGEF3 was determined by evaluating the effects of wild\u2010type or GEF\u2010inactive ARHGEF3 overexpression with ROCK inhibitor treatment. To gain more mechanistic insights, autophagy flux and the role of autophagy were assessed in various conditions with chloroquine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Inhibition of ROCK with Y\u201027632 improved muscle force production in 3D\u2010engineered <jats:italic>mdx<\/jats:italic> muscles (+25% from three independent experiments, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and in mice (+25%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). Unlike suggested by previous studies, this improvement was independent of muscle differentiation or quantity and instead related to increased muscle quality. We found that ARHGEF3 was elevated and responsible for RhoA\/ROCK activation in <jats:italic>mdx<\/jats:italic> muscles, and that depleting ARHGEF3 in <jats:italic>mdx<\/jats:italic> mice restored muscle quality (up to +36%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and morphology without affecting regeneration. Conversely, overexpressing ARHGEF3 further compromised <jats:italic>mdx<\/jats:italic> muscle quality (\u221213% vs. empty vector control, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) in GEF activity\u2010 and ROCK\u2010dependent manner. Notably, ARHGEF3\/ROCK inhibition exerted the effects by rescuing autophagy which is commonly impaired in dystrophic muscles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings uncover a new pathological mechanism of muscle weakness in DMD involving the ARHGEF3\u2010ROCK\u2010autophagy pathway and the therapeutic potential of targeting ARHGEF3 in DMD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13278","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T00:48:01Z","timestamp":1686703681000},"page":"1880-1893","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["RhoA\/ROCK signalling activated by ARHGEF3 promotes muscle weakness via autophagy in dystrophic <i>mdx<\/i> mice"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7791-8563","authenticated-orcid":false,"given":"Jae\u2010Sung","family":"You","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology University of Illinois at Urbana\u2010Champaign  Urbana Illinois USA"},{"name":"Department of Bioengineering University of Illinois at Urbana\u2013Champaign  Urbana Illinois USA"},{"name":"Nick J. Holonyak Micro and Nanotechnology Laboratory University of Illinois at Urbana\u2013Champaign  Urbana Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongdeok","family":"Kim","sequence":"additional","affiliation":[{"name":"Nick J. Holonyak Micro and Nanotechnology Laboratory University of Illinois at Urbana\u2013Champaign  Urbana Illinois USA"},{"name":"Department of Materials Science and Engineering University of Illinois at Urbana\u2013Champaign  Urbana Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2289-6076","authenticated-orcid":false,"given":"Soohyun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology University of Illinois at Urbana\u2010Champaign  Urbana Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashid","family":"Bashir","sequence":"additional","affiliation":[{"name":"Department of Bioengineering University of Illinois at Urbana\u2013Champaign  Urbana Illinois USA"},{"name":"Nick J. Holonyak Micro and Nanotechnology Laboratory University of Illinois at Urbana\u2013Champaign  Urbana Illinois USA"},{"name":"Department of Materials Science and Engineering University of Illinois at Urbana\u2013Champaign  Urbana Illinois USA"},{"name":"Department of Mechanical Science and Engineering University of Illinois at Urbana\u2013Champaign  Urbana Illinois USA"},{"name":"Department of Biomedical and Translational Sciences Carle Illinois College of Medicine  Urbana Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7887-3747","authenticated-orcid":false,"given":"Jie","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology University of Illinois at Urbana\u2010Champaign  Urbana Illinois 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