The G protein-coupled receptor ligand apelin-13 ameliorates skeletal muscle atrophy induced by chronic kidney disease.

Abstract

BACKGROUND:

Targeting of the apelin-apelin receptor (Apj) system may serve as a useful therapeutic intervention for the management of chronic kidney disease (CKD)-induced skeletal muscle atrophy. We investigated the roles and efficacy of the apelin-Apj system in CKD-induced skeletal muscle atrophy.

METHODS:

The 5/6-nephrectomized mice were used as CKD models. AST-120, a charcoal adsorbent of uraemic toxins (8 w/w% in diet), or apelin (1 μmol/kg) was administered to CKD mice to investigate the mechanism and therapeutic potential of apelin on CKD-induced skeletal muscle atrophy. The effect of indoxyl sulfate, a uraemic toxin, or apelin on skeletal muscle atrophy was evaluated using mouse myoblast cells (C2C12 cells) in vitro.

RESULTS:

Skeletal muscle atrophy developed over time following nephrectomy at 12 weeks, as confirmed by a significant increase of atrogin-1 and myostatin mRNA expression in the gastrocnemius (GA) muscle and a decrease of lower limb skeletal muscle weight (P < 0.05, 0.01 and 0.05, respectively). Apelin expression in GA muscle was significantly decreased (P < 0.05) and elabela, another Apj endogenous ligand, tended to show a non-significant decrease at 12 weeks after nephrectomy. Administration of AST-120 inhibited the decline of muscle weight and increase of atrogin-1 and myostatin expression. Apelin and elabela expression was slightly improved by AST-120 administration but Apj expression was not, suggesting the involvement of uraemic toxins in endogenous Apj ligand expression. The administration of apelin at 1.0 μmol/kg for 4 weeks to CKD mice suppressed the increase of atrogin-1 and myostatin, increased apelin and Apj mRNA expression at 30 min after apelin administration and significantly ameliorated weight loss and a decrease of the cross-sectional area of hindlimb skeletal muscle.

CONCLUSIONS:

This study demonstrated for the first time the association of the Apj endogenous ligand-uraemic toxin axis with skeletal muscle atrophy in CKD and the utility of therapeutic targeting of the apelin-Apj system.

• Authors: Yuki Enoki, Tomoya Nagai, Yuna Hamamura, Sumika Osa, Hideaki Nakamura, Kazuaki Taguchi, Hiroshi Watanabe, Toru Maruyama, Kazuaki Matsumoto
• Journal: Journal of cachexia, sarcopenia and muscle (J Cachexia Sarcopenia Muscle) Vol. 14 Issue 1 Pg. 553-564 (02 2023) ISSN: 2190-6009 [Electronic] Germany
• PMID: 36562292 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.

Chemical References

• apelin-13 peptide
• Apelin
• AST 120
• Myostatin
• Ligands
• Uremic Toxins
• Apelin Receptors
• RNA, Messenger

Topics

• Mice
• Animals
• Apelin (pharmacology, therapeutic use, metabolism)
• Myostatin (metabolism)
• Ligands
• Uremic Toxins
• Muscle, Skeletal (pathology)
• Apelin Receptors (genetics, metabolism)
• Muscular Atrophy (drug therapy, etiology, metabolism)
• Renal Insufficiency, Chronic (drug therapy, etiology, metabolism)
• RNA, Messenger (metabolism)