Moderated Poster

Poster, Podium & Video Sessions

MP42-09: Atrogin is a Novel Marker of Age-Related Urethral Sphincter Muscle Atrophy

Saturday, May 13
3:30 PM - 5:30 PM
Location: BCEC: Room 160

Presentation Authors: M. Raj Rajasekaran*, Johnny Fu, My-Uyen (Lilly) Nguyen, Valmik Bhargava, San Diego, CA

Introduction: Previous studies show an age-related increase in the prevalence of urinary incontinence (UI) (10-15% in adults and ~30% % in older population >70 years). Age-related atrophic changes in urethral sphincter muscles are recognized as the most common cause for UI in the geriatric population. Recently, atrogin (a muscle-specific E3 ubiquitin ligase) is recognized as an important molecular pathway involved in age-related muscle atrophy. We tested the hypothesis that increased urethral sphincter atrophy during advanced aging is mediated by this novel atrogin pathway.



Methods: We used a rabbit model to establish time course of age-related urethral sphincter muscle complex dysfunction and for further evaluation of molecular mechanisms of muscle dysfunction /atrophy in rabbits. We employed young (6-9 months), middle age (>12 months) and old rabbits (>30 months) and measured urethral muscle thickness (using transurethral ultrasound (US) technique (Fig A-inset) as well as urethral closure pressure (Fig A) in response to pelvic floor muscle electrical stimulation. We harvested bladder neck (for lissosphincter) and mid-urethra (for rhabdosphincter) samples to evaluate protein and mRNA levels of atrogin (marker of atrophy) using Western blot (protein) /qPCR studies respectively.

Results: Our rabbit studies confirmed age-related changes in the urethral sphincter muscle thickness (Fig A) and alterations in closure pressure (Fig A) as well as in protein/mRNA levels of marker of atrophy (atrogin; Fig B-D) in both bladder neck and mid-urethra . These observations confirm our hypothesis that age-related increase in atrophy mediated via atrogin pathway may contribute to sphincter muscle dysfunction.

Conclusions: Our physiological, imaging and molecular studies are consistent with our hypothesis that age-related increase in atrogin protein contribute to sphincter muscle dysfunction. Targeting atrogin may be a novel approach to prevent age-related urethral sphincter muscle atrophy.

Source Of Funding: VA Rehabilitation Research Merit Award

M. Raj Rajasekaran, PHD

UCSD



Dr. Rajasekaran, PhD, is a Research Pharmacologist at San Diego Veterans Hospital and an Associate Professor of Surgery at the University of California San Diego Medical Center, San Diego, California, USA.

Dr. Rajasekaran received his PhD from the University of Madras, Department of Pharmacology, India. He has focused his research on stem cell biology, tissue regeneration, incontinence and reproductive toxicology. His current areas of research include development of animal models for urinary and fecal incontinence, stem therapy for urological disorders, mechanism of age-related male sexual dysfunction.

As an accomplished Pharmacology Scientist for over 25 years, Dr. Rajasekaran has received national and international recognition for research. This includes prestigious awards, such as, the Uvnas prize for best publication in Immunopharmacology, and a national scholar award from the American Urological Association. During this time, he has made numerous contributions to Pharmacological research, beginning with establishment of the first in-vitro cell culture model in the year 2000, followed by stem cell research in this area. These models have brought in substantial funding from the drug industry. As an academic researcher, he has also served as principal/co-investigator of US- federal and industry funded contract projects working with Medicinova Inc, Myogen Inc, Acetlion Pharmaceuticals, Vivus Inc, cook Urological and Pharmacia & Upjohn. This has led to IND submissions with the FDA and clinical trials.


Dr. Rajasekaran. has authored over 60 articles in these areas, which have been published in journals including American Journal of Physiology, The Journal of Urology, Urology, the Journal of Andrology, and the International Journal of Andrology. His abstracts have been presented at meetings of the American Urological Association (AUA) and the International Society of Andrology on many topics, including stem cell applications for genito-urinary disorders.

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