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

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.