{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T14:30:38Z","timestamp":1789396238593,"version":"build-2803163510"},"reference-count":72,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:00:00Z","timestamp":1760140800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF18OC0033438"],"award-info":[{"award-number":["NNF18OC0033438"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004710","name":"Fondazione Umberto Veronesi","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004710","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>MicroRNA-22 (miR-22) is a negative regulator of mitochondrial biogenesis, as well as lipid and glucose metabolism, in metabolically active tissues. Silencing miR-22 holds promise as a potential treatment of obesity and metabolic syndrome, as it restores metabolic capacity\u2014enhancing oxidative metabolism\u2014and reduces ectopic fat accumulation in chronic obesity, a driver of impaired metabolic flexibility and muscle mass loss. Intramuscular adipose accumulation and defective mitochondrial function are features associated with obese-mediated muscle atrophy and hallmarks of neuromuscular disorders such as Duchenne muscular dystrophy. Therefore, miR-22 could represent a compelling molecular target to improve muscle health across various muscle-wasting conditions. This study describes a pharmacological strategy for the inhibition of miR-22 in skeletal muscle by employing a mixmer antisense oligonucleotide (ASO, anti-miR-22). Administration of the ASO in a mouse model of obesity positively modulated myogenesis while protecting dystrophic mice from muscle function decline, enhancing fatigue resistance, and limiting pathological fibrotic remodeling. Mechanistically, we show that anti-miR-22 treatment promotes derepression of genes involved in mitochondrial homeostasis, favoring oxidative fiber content regardless of the disease model, thus promoting a more resilient phenotype. Furthermore, we suggest that miR-22 inhibition increases autophagy by transcriptional activation of multiple negative regulators of mammalian target of rapamycin (mTOR) signaling to decrease immune infiltration and fibrosis. These findings position miR-22 as a promising therapeutic target for muscle atrophy and support its potential to restore muscle health.<\/jats:p>","DOI":"10.3390\/ijms26209900","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T16:13:03Z","timestamp":1760717583000},"page":"9900","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["microRNA-22 Inhibition Stimulates Mitochondrial Homeostasis and Intracellular Degradation Pathways to Prevent Muscle Wasting"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4136-8754","authenticated-orcid":false,"given":"Simone","family":"Tomasini","sequence":"first","affiliation":[{"name":"Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, 2450 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7440-900X","authenticated-orcid":false,"given":"Emanuele","family":"Monteleone","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Systems Biology, University of Turin, 10124 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Altieri","sequence":"additional","affiliation":[{"name":"Resalis Therapeutics Srl, Via E. De Sonnaz 19, 10121 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4172-2478","authenticated-orcid":false,"given":"Francesco","family":"Margiotta","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale G. Pieraccini 6, 50139 Firenze, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fereshteh","family":"Dardmeh","sequence":"additional","affiliation":[{"name":"Department of Health Science and Technology, Aalborg University, 9220 Aalborg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8500-4208","authenticated-orcid":false,"given":"Hiva","family":"Alipour","sequence":"additional","affiliation":[{"name":"Department of Health Science and Technology, Aalborg University, 9220 Aalborg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8796-1872","authenticated-orcid":false,"given":"Anja","family":"Holm","sequence":"additional","affiliation":[{"name":"RNA Therapeutics, Translational Research Centre, Rigshospitalet, 2600 Glostrup, Denmark"},{"name":"Cell and Drug Technologies, Department of Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakari","family":"Kauppinen","sequence":"additional","affiliation":[{"name":"Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, 2450 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Panella","sequence":"additional","affiliation":[{"name":"Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, 2450 Copenhagen, Denmark"},{"name":"Resalis Therapeutics Srl, Via E. De Sonnaz 19, 10121 Torino, Italy"},{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale G. Pieraccini 6, 50139 Firenze, Italy"},{"name":"European Biomedical Research Institute of Salerno (EBRIS), Via Salvatore de Renzi 50, 84125 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mukund, K., and Subramaniam, S. (2020). Skeletal muscle: A review of molecular structure and function, in health and disease. Wiley Interdiscip. Rev. Syst. Biol. Med., 12.","DOI":"10.1002\/wsbm.1462"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1152\/physrev.00040.2020","article-title":"Energy metabolism design of the striated muscle cell","volume":"101","author":"Glancy","year":"2021","journal-title":"Physiol. 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