Therapeutic potential of muscle growth promoters in a stress urinary incontinence model

Author:

Yang Jun12,Balog Brian13,Deng Kangli13,Hanzlicek Brett13,Rietsch Anna13,Kuang Mei13,Hatakeyama Shinji4,Lach-Trifilieff Estelle4,Zhu Hui35,Damaser Margot S.135ORCID

Affiliation:

1. Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio

2. Department of Urology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China

3. Advanced Platform Technology Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio

4. Novartis Institutes for BioMedical Research, Novartis pharma AG, Basel, Switzerland

5. Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, Ohio

Abstract

Weakness of urinary sphincter and pelvic floor muscles can cause insufficient urethral closure and lead to stress urinary incontinence. Bimagrumab is a novel myostatin inhibitor that blocks activin type II receptors, inducing skeletal muscle hypertrophy and attenuating muscle weakness. β2-Adrenergic agonists, such as 5-hydroxybenzothiazolone derivative (5-HOB) and clenbuterol, can enhance muscle growth. We hypothesized that promoting muscle growth would increase leak point pressure (LPP) by facilitating muscle recovery in a dual-injury (DI) stress urinary incontinence model. Rats underwent pudendal nerve crush (PNC) followed by vaginal distension (VD). One week after injury, each rat began subcutaneous (0.3 mL/rat) treatment daily in a blinded fashion with either bimagrumab (DI + Bim), clenbuterol (DI + Clen), 5-HOB (DI + 5-HOB), or PBS (DI + PBS). Sham-injured rats underwent sham PNC + VD and received PBS (sham + PBS). After 2 wk of treatment, rats were anesthetized for LPP and external urethral sphincter electromyography recordings. Hindlimb skeletal muscles and pelvic floor muscles were dissected and stained. At the end of 2 wk of treatment, all three treatment groups had a significant increase in body weight and individual muscle weight compared with both sham-treated and sham-injured rats. LPP in DI + Bim rats was significantly higher than LPP of DI + PBS and DI + Clen rats. There were more consistent urethral striated muscle fibers, elastin fibers in the urethra, and pelvic muscle recovery in DI + Bim rats compared with DI + PBS rats. In conclusion, bimagrumab was the most effective for increasing urethral pressure and continence by promoting injured external urethral sphincter and pelvic floor muscle recovery.

Funder

Novartis Institutes for Biomedical Research

Cleveland Clinic

Publisher

American Physiological Society

Subject

Physiology

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