{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T21:15:12Z","timestamp":1774991712272,"version":"3.50.1"},"reference-count":36,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T00:00:00Z","timestamp":1627344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder, affecting one in 3500 to 5000 boys worldwide. The NO-sGC-cGMP pathway plays an important role in skeletal muscle function, primarily by improving blood flow and oxygen supply to the muscles during exercise. In fact, PDE5 inhibitors have previously been investigated as a potential therapy for DMD, however, a large-scale Phase III clinical trial did not meet its primary endpoint. Since the efficacy of PDE5i is dependent on sufficient endogenous NO production, which might be impaired in DMD, we investigated if NO-independent sGC stimulators, could have therapeutic benefits in a mouse model of DMD. Male mdx\/mTRG2 mice aged six weeks were given food supplemented with the sGC stimulator, BAY-747 (150 mg\/kg of food) or food alone (untreated) ad libitum for 16 weeks. Untreated C57BL6\/J mice were used as wild type (WT) controls. Assessments of the four-limb hang, grip strength, running wheel and serum creatine kinase (CK) levels showed that mdx\/mTRG2 mice had significantly reduced skeletal muscle function and severe muscle damage compared to WT mice. Treatment with BAY-747 improved grip strength and running speed, and these mice also had reduced CK levels compared to untreated mdx\/mTRG2 mice. We also observed increased inflammation and fibrosis in the skeletal muscle of mdx\/mTRG2 mice compared to WT. While gene expression of pro-inflammatory cytokines and some pro-fibrotic markers in the skeletal muscle was reduced following BAY-747 treatment, there was no reduction in infiltration of myeloid immune cells nor collagen deposition. In conclusion, treatment with BAY-747 significantly improves several functional and pathological parameters of the skeletal muscle in mdx\/mTRG2 mice. However, the effect size was moderate and therefore, more studies are needed to fully understand the potential treatment benefit of sGC stimulators in DMD.<\/jats:p>","DOI":"10.3390\/ijms22158016","type":"journal-article","created":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T12:18:31Z","timestamp":1627388311000},"page":"8016","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Assessing the Use of the sGC Stimulator BAY-747, as a Potential Treatment for Duchenne Muscular Dystrophy"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7642-6708","authenticated-orcid":false,"given":"Shalini Murali","family":"Krishnan","sequence":"first","affiliation":[{"name":"Bayer AG, R&D Pharmaceuticals, Pharma Research Center, 42113 Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"Nordlohne","sequence":"additional","affiliation":[{"name":"Bayer AG, R&D Pharmaceuticals, Pharma Research Center, 42113 Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Dietz","sequence":"additional","affiliation":[{"name":"Bayer AG, R&D Pharmaceuticals, Pharma Research Center, 42113 Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandros","family":"Vakalopoulos","sequence":"additional","affiliation":[{"name":"Bayer AG, R&D Pharmaceuticals, Pharma Research Center, 42113 Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Haning","sequence":"additional","affiliation":[{"name":"Bayer AG, R&D Pharmaceuticals, Pharma Research Center, 42113 Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elke","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Bayer AG, R&D Pharmaceuticals, Pharma Research Center, 42113 Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roland","family":"Seifert","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7261-7171","authenticated-orcid":false,"given":"J\u00f6rg","family":"H\u00fcser","sequence":"additional","affiliation":[{"name":"Bayer AG, R&D Pharmaceuticals, Pharma Research Center, 42113 Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilka","family":"Mathar","sequence":"additional","affiliation":[{"name":"Bayer AG, R&D Pharmaceuticals, Pharma Research Center, 42113 Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2977-7553","authenticated-orcid":false,"given":"Peter","family":"Sandner","sequence":"additional","affiliation":[{"name":"Bayer AG, R&D Pharmaceuticals, Pharma Research Center, 42113 Wuppertal, Germany"},{"name":"Institute of Pharmacology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Sun, C., Shen, L., Zhang, Z., and Xie, X. (2020). Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update. Genes, 11.","DOI":"10.3390\/genes11080837"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S1474-4422(18)30025-5","article-title":"Diagnosis and management of Duchenne muscular dystrophy, part 2: Respiratory, cardiac, bone health, and orthopaedic management","volume":"17","author":"Birnkrant","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S1474-4422(18)30024-3","article-title":"Diagnosis and management of Duchenne muscular dystrophy, part 1: Diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management","volume":"17","author":"Birnkrant","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S1474-4422(18)30026-7","article-title":"Diagnosis and management of Duchenne muscular dystrophy, part 3: Primary care, emergency management, psychosocial care, and transitions of care across the lifespan","volume":"17","author":"Birnkrant","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1007\/s43440-020-00134-x","article-title":"Muscle and cardiac therapeutic strategies for Duchenne muscular dystrophy: Past, present, and future","volume":"72","author":"Loboda","year":"2020","journal-title":"Pharmacol. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/j.nmd.2018.09.001","article-title":"Role of neuronal nitric oxide synthase (nNOS) in Duchenne and Becker muscular dystrophies\u2014Still a possible treatment modality?","volume":"28","author":"Dombernowsky","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1089\/ars.2016.6630","article-title":"Nitric Oxide Regulates Skeletal Muscle Fatigue, Fiber Type, Microtubule Organization, and Mitochondrial ATP Synthesis Efficiency Through cGMP-Dependent Mechanisms","volume":"26","author":"Moon","year":"2017","journal-title":"Antioxid. Redox Signal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13818","DOI":"10.1073\/pnas.250379497","article-title":"Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy","volume":"97","author":"Sander","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1146\/annurev-nutr-082117-051622","article-title":"Dietary Nitrate and Physical Performance","volume":"38","author":"Jones","year":"2018","journal-title":"Annu. Rev. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Asai, A., Sahani, N., Kaneki, M., Ouchi, Y., Martyn, J.A., and Yasuhara, S.E. (2007). Primary role of functional ischemia, quantitative evidence for the two-hit mechanism, and phosphodiesterase-5 inhibitor therapy in mouse muscular dystrophy. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000806"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"19079","DOI":"10.1073\/pnas.1013077107","article-title":"Sildenafil reverses cardiac dysfunction in the mdx mouse model of Duchenne muscular dystrophy","volume":"107","author":"Adamo","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Hammers, D.W., Sleeper, M.M., Forbes, S.C., Shima, A., Walter, G.A., and Sweeney, H.L. (2016). Tadalafil Treatment Delays the Onset of Cardiomyopathy in Dystrophin-Deficient Hearts. J. Am. Heart Assoc., 5.","DOI":"10.1161\/JAHA.116.003911"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1002\/path.4054","article-title":"Sildenafil reduces respiratory muscle weakness and fibrosis in the mdx mouse model of Duchenne muscular dystrophy","volume":"228","author":"Percival","year":"2012","journal-title":"J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1212\/WNL.0000000000000498","article-title":"PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy","volume":"82","author":"Nelson","year":"2014","journal-title":"Neurology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"162ra155","DOI":"10.1126\/scitranslmed.3004327","article-title":"Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy","volume":"4","author":"Martin","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1212\/WNL.0000000000004570","article-title":"A phase 3 randomized placebo-controlled trial of tadalafil for Duchenne muscular dystrophy","volume":"89","author":"Victor","year":"2017","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/35065611","article-title":"NO-independent regulatory site on soluble guanylate cyclase","volume":"410","author":"Stasch","year":"2001","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/sj.bjp.0704778","article-title":"NO- and haem-independent activation of soluble guanylyl cyclase: Molecular basis and cardiovascular implications of a new pharmacological principle","volume":"136","author":"Stasch","year":"2002","journal-title":"Br. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1002\/cmdc.200900014","article-title":"Discovery of riociguat (BAY 63-2521): A potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension","volume":"4","author":"Mittendorf","year":"2009","journal-title":"ChemMedChem"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/978-3-642-38664-0_12","article-title":"Soluble guanylate cyclase stimulators in pulmonary hypertension","volume":"218","author":"Stasch","year":"2013","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4627","DOI":"10.1113\/jphysiol.2014.274878","article-title":"Nitric oxide synthase deficiency and the pathophysiology of muscular dystrophy","volume":"592","author":"Tidball","year":"2014","journal-title":"J. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/nature07414","article-title":"Sarcolemma-localized nNOS is required to maintain activity after mild exercise","volume":"456","author":"Kobayashi","year":"2008","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1093\/bmb\/ldm014","article-title":"Creatine kinase monitoring in sport medicine","volume":"81\u201382","author":"Brancaccio","year":"2007","journal-title":"Br. Med. Bull."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5146","DOI":"10.1021\/acs.jmedchem.7b00449","article-title":"Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure","volume":"60","author":"Follmann","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Vitiello, L., Tibaudo, L., Pegoraro, E., Bello, L., and Canton, M. (2019). Teaching an Old Molecule New Tricks: Drug Repositioning for Duchenne Muscular Dystrophy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20236053"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/ncb2790","article-title":"Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy","volume":"15","author":"Mourkioti","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Yucel, N., Chang, A.C., Day, J.W., Rosenthal, N., and Blau, H.M. (2018). Humanizing the mdx mouse model of DMD: The long and the short of it. NPJ Regen. Med., 3.","DOI":"10.1038\/s41536-018-0045-4"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"West, J.D., Galindo, C.L., Kim, K., Shin, J.J., Atkinson, J.B., Macias-Perez, I., Pavliv, L., Knollmann, B.C., Soslow, J.H., and Markham, L.W. (2019). Antagonism of the Thromboxane-Prostanoid Receptor as a Potential Therapy for Cardiomyopathy of Muscular Dystrophy. J. Am. Heart Assoc., 8.","DOI":"10.1161\/JAHA.118.011902"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5323","DOI":"10.1021\/acs.jmedchem.0c02154","article-title":"Discovery of the Soluble Guanylate Cyclase Activator Runcaciguat (BAY 1101042)","volume":"64","author":"Hahn","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1093\/ptj\/81.11.1810","article-title":"Human skeletal muscle fiber type classifications","volume":"81","author":"Scott","year":"2001","journal-title":"Phys. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Rad\u00e1k, Z. (2018). Skeletal Muscle, Function, and Muscle Fiber Types. The Physiology of Physical Training, Academic Press.","DOI":"10.1016\/B978-0-12-815137-2.00002-4"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1161\/CIRCULATIONAHA.111.031716","article-title":"Early treatment with lisinopril and spironolactone preserves cardiac and skeletal muscle in Duchenne muscular dystrophy mice","volume":"124","author":"Chimanji","year":"2011","journal-title":"Circulation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/j.cell.2010.11.039","article-title":"Short telomeres and stem cell exhaustion model Duchenne muscular dystrophy in mdx\/mTR mice","volume":"143","author":"Sacco","year":"2010","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1016\/j.bbrc.2013.12.108","article-title":"Nucleotidyl cyclase activity of soluble guanylyl cyclase in intact cells","volume":"443","author":"Bahre","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3469","DOI":"10.1016\/j.febslet.2014.08.005","article-title":"PDE7A1 hydrolyzes cCMP","volume":"588","author":"Monzel","year":"2014","journal-title":"FEBS Lett."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/15\/8016\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:35:35Z","timestamp":1760164535000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/15\/8016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,27]]},"references-count":36,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22158016"],"URL":"https:\/\/doi.org\/10.3390\/ijms22158016","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,27]]}}}