Soluble guanylate cyclase stimulator vericiguat alleviates skeletal muscle injury and exercise capacity decline in ApoE-/- mice by inhibiting oxidative stress and repairing mitophagy.

Patients with atherosclerosis suffer from exercise capacity decline and skeletal muscle injury. Soluble guanylate cyclase stimulator vericiguat plays a protective role in the blood vessels and kidneys in addition to treating heart failure, but its effect on skeletal muscles remains unclear. This study aimed to investigated whether vericiguat can improve exercise capacity and mitigate skeletal muscle injury of atherosclerotic ApoE-/- mice. Vericiguat dose-dependently increased the forelimb grip strength, hanging impulse, and exhaustive running time, and reduced the levels of creatine kinase and lactatedehydrogenase, independently of improvements in plaque burden. In vericiguat group, the expression level of cGMP and PKG1α, the cross sectional area of skeletal muscles and the proportion of slow myofibers were dose-dependently increased. Vericiguat reduced the level of IL-6, TNF-α and MitoROS in skeletal muscles, and increased the level of SOD, GSH/GSSG ratio, mitochondrial content and membrane potential. In the mitophagy signaling pathway, the expression of p62 in skeletal muscles was decreased in vericiguat group, while the expression of PINK, Parkin, and LC3-II/I was increased. This study found that vericiguat could improve exercise capacity and mitigate skeletal muscle injury of atherosclerotic mice by repairing the impaired sGC-cGMP-PKG pathway, along with reducing skeletal muscle atrophy, inflammation and oxidative stress, and improving mitochondrial function and mitophagy.