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

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

  • Biochem Pharmacol. 2025 Dec 5:245:117570. doi: 10.1016/j.bcp.2025.117570.
Yu-Lin Li 1,  Bo-Ang Hu 2,  Puyuan Xiao 3,  Lu Han 4,  Zhou-Jie Tong 5,  Xu Jia 6,  Ya-Qiong Jiao 3,  Ming Song 7,  Zhi-Hao Wang 6,  Wei Zhang 3,  Yuan-Yuan Shang 8,  Ming Zhong 9
Affiliations

Affiliations

  • 1 State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
  • 2 State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Geriatric Medicine, Qilu Hospital of Shandong University, Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan 250012, China.
  • 3 State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, China.
  • 4 State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, China; Department of General Practice, Qilu Hospital of Shandong University, Jinan 250012, China.
  • 5 Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
  • 6 Department of Geriatric Medicine, Qilu Hospital of Shandong University, Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan 250012, China.
  • 7 National Medicine-Engineering Interdisciplinary Industry-Education Integration Innovation Platform, Shandong Key Laboratory: Magnetic Field-free Medicine & Functional Imaging, Research Institute of Shandong University: Magnetic Field-free Medicine & Functional Imaging, Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan 250012, China.
  • 8 State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address: [email protected].
  • 9 State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address: [email protected].
PMID: 41354362 DOI: 10.1016/j.bcp.2025.117570
Abstract

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.

Keywords

Atherosclerosis; Mitophagy; Oxidative Stress; Skeletal Muscle; Vericiguat.

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