miR-133a deficiency is associated with cardiac and skeletal muscle remodeling and enhanced Fosl-2/TGF-β1/Smad3-related profibrotic signaling in ischemic heart failure

Exercise intolerance in heart failure (HF) reflects combined cardiac and skeletal muscle abnormalities, but the molecular associations underlying concurrent remodeling remain unclear. We examined cardiac and skeletal muscle phenotypes in a rat model of ischemic HF with global miR-133a deficiency and explored candidate downstream signaling. Cardiac function, exercise tolerance, myofiber morphology, and tissue fibrosis were assessed using echocardiography, functional tests, and histopathology. miR-133a-3p , a mature miRNA derived from pre-miR-133a , was selected for expression and target analyses. RNA sequencing, bioinformatic analysis, qRT-PCR, immunoblotting, and dual-luciferase assays were used to investigate candidate molecular relationships. miR-133a-3p expression decreased in myocardial and gastrocnemius tissues after HF induction. miR-133a -deficient rats showed no overt baseline differences in body weight or cardiac function but developed greater cardiac dysfunction, exercise intolerance, myofiber atrophy, and collagen deposition after HF induction. Transcriptomic and bioinformatic analyses prioritized Fosl-2 as a candidate downstream target. miR-133a-3p regulated the Fosl-2 3′ UTR reporter in a binding-site-dependent manner, while miR-133a deficiency was accompanied by increased Fosl-2 expression and enhanced TGF-β1/Smad3-associated profibrotic signaling in both tissues. These findings associate miR-133a deficiency with concurrent cardiac and skeletal muscle remodeling in ischemic HF and support the involvement of altered Fosl-2 expression and profibrotic signaling.