Kidney Week

Abstract: TH-OR33

Exercise Mimetic Restores Muscle and Bone Outcomes in a Rat Model of CKD

Session Information

• CKD-MBD and Kidney Stones: Novel Insights
  October 24, 2024 | Location: Room 6D, Convention Center
  Abstract Time: 05:20 PM - 05:30 PM

Category: Bone and Mineral Metabolism

• 501 Bone and Mineral Metabolism: Basic

Authors

• Troutman, Ashley Danielle, Indiana University, Department of Physical Therapy, Indianapolis, Indiana, United States

Ashley Danielle Troutman

• Chen, Neal X., Indiana University School of Medicine, Indianapolis, Indiana, United States

Neal X. Chen, PhD

• Srinivasan, Shruthi, Indiana University School of Medicine, Indianapolis, Indiana, United States

Shruthi Srinivasan, MS

• Metzger, Corinne E., Indiana University School of Medicine, Indianapolis, Indiana, United States

Corinne E. Metzger, PhD

• O'Neill, Kalisha, Indiana University School of Medicine, Indianapolis, Indiana, United States

Kalisha O'Neill

• Tak, Landon, Indiana University School of Medicine, Indianapolis, Indiana, United States

Landon Tak, MS

• Schulte, Michael, Indiana University School of Medicine, Indianapolis, Indiana, United States

Michael Schulte, PhD

• Moe, Sharon M., Indiana University School of Medicine, Indianapolis, Indiana, United States

Sharon M. Moe, MD, FASN

• Avin, Keith G., Indiana University School of Medicine, Indianapolis, Indiana, United States

Keith G. Avin, PhD

Background

Chronic kidney disease (CKD) progressively deteriorates skeletal muscle and bone leading to sarcopenia and CKD-bone mineral disease (CKD-MBD). Exercise studies have demonstrated variable success, which supports the need for pharmacological interventions. We used an investigational drug, Locamidazole (LAMZ), with documented muscle and bone anabolic effects that mimic exercise. We hypothesized that LAMZ would improve physical function and bone outcomes in a rat model of CKD.

Methods

We used a naturally occurring and progressive rat model of CKD (Cy/+; n=10-12/gr): 1) normal littermates (NL), 2) Cy/+ (CKD), and 3) CKD-LAMZ (LAMZ). LAMZ s.q. injections, 2x/day at 0.625mg/kg for 5 weeks, beginning at 27 weeks (CKD stage 3). At 33 weeks (end-stage renal disease), rats were terminated for specimen collection. Outcomes: serum biochemistry, electrically stimulated muscle strength and fatigue (series of 50 muscle contractions), maximal running distance, bone microarchitecture, and vascular calcification. Data analysis included one-way ANOVA with Tukey’s multiple comparisons test.

Results

Disease Effects (CKD vs NL)- CKD was confirmed via elevated blood urea nitrogen (BUN; p<0.0001) and creatinine (p<0.0001), muscle weakness (p<0.05), muscle fatigue (p<0.01), lower running distance (p<0.05), increased cortical bone porosity (p<0.001), and reduced cortical bone area (p<0.01), and cortical thickness (p<0.001). LAMZ Effects (CKD-LAMZ vs CKD)- LAMZ did not impact disease progression. LAMZ improved muscle function with significantly improved maximally stimulated muscle strength (p<0.05) and trending improvements for electrically stimulated muscle fatigue (p=0.08). LAMZ improved bone health with reduced cortical porosity (p<0.01) and increased cortical thickness (p<0.01). Maximal running distance demonstrated an intermediate level of adaptation (i.e., not statistically different from NL or CKD); additional samples pending for biochemistry and vascular calcification.

Conclusion

LAMZ administered for 5 weeks significantly improved both muscle strength and bone microarchitecture. The potential for an exercise mimetic is exciting for nephrologists and patients with CKD alike, as an alternative method to improve musculoskeletal health and quality of life.

Funding

• Other NIH Support