Downregulation of S100a8 mitigates fibrosis in skeletal muscles affected by Marfan syndrome

Audrei R Santos; Marcelo G Pereira; Andrei Rozanski; Cesar S Fuziwara; Tabata L Nascimento; Lygia V Pereira; Marcelo S Aoki; Elen H Miyabara

doi:10.1016/j.omtn.2026.102846

Downregulation of S100a8 mitigates fibrosis in skeletal muscles affected by Marfan syndrome

Mol Ther Nucleic Acids. 2026 Jan 24;37(1):102846. doi: 10.1016/j.omtn.2026.102846. eCollection 2026 Mar 12.

Authors

Audrei R Santos¹, Marcelo G Pereira¹, Andrei Rozanski¹, Cesar S Fuziwara^{2

3}, Tabata L Nascimento¹, Lygia V Pereira⁴, Marcelo S Aoki⁵, Elen H Miyabara¹

Affiliations

¹ Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil.
² Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil.
³ Department of Biochemistry, Federal University of Sao Paulo, São Paulo 04044-020, Brazil.
⁴ Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo, São Paulo 05508-090, Brazil.
⁵ School of Arts, Sciences and Humanities, University of São Paulo, São Paulo 03828-000, Brazil.

Abstract

This study investigated the potential of eccentric training in attenuating the deleterious effects of Marfan syndrome on skeletal muscles. Marfan syndrome and wild-type mice were divided into a trained and a control group; the former performed a downhill running protocol for 8 weeks. Morphological, molecular, and functional analyses were performed. Based on RNA sequencing analyses, the gastrocnemius and plantaris muscles were transfected with S100a8-shRNA (short hairpin RNA) and analyzed after 21 days. The muscle wet weight normalized to body weight and the percentage of myofibers with a higher cross-sectional area were lower in the muscles of Marfan syndrome mice than in wild-type mice. Marfan syndrome mice showed increased fibrosis and number of rounded myofibers, whereas eccentric training reduced these effects. Muscle-specific force was unaltered across groups. In addition, Marfan syndrome mice presented an increase in the number of CD11b⁺ myeloid cells and the mRNA levels of calcium-binding proteins S100a8 and S100a9 and cytokines Tnfa, Il6, and Il10 in muscles, while eccentric training reversed these effects. The knockdown of S100a8 induced by in vivo S100a8-shRNA transfection decreased muscle fibrosis in Marfan syndrome mice. In summary, eccentric training and knockdown of S100a8 are beneficial to reducing fibrosis in muscles affected by Marfan syndrome.

Keywords: MT: Oligonucleotides: Therapies and Applications; calcium-binding protein; connective tissue; cytokines; eccentric exercise; fibrillin-1; maximum tetanic force; muscle transfection; myopathy; shRNA; transcriptome.