Chronic kidney disease (CKD) affects 20 million Americans and contributes to sarcopenia, which includes muscle loss (atrophy), muscle weakness and/or reduced mobility. Sarcopenia is clinically important as it contributes to increased fall risk, morbidity and mortality. Although, the pathophysiology of sarcopenia in CKD remains unknown, sarcopenia in CKD is likely due to aberrant signaling for muscle metabolism, catabolism, and regeneration. We propose that central components of these to sarcopenic alterations are impaired skeletal muscle mitochondria and increased myostatin. The overall goal of this proposal is to test the hypothesis that exercise or myostatin blocking therapy prevents atrophy, but exercise is needed to improve skeletal muscle metabolism and function in CKD. This goal will be accomplished through a combination of pre- clinical experiments using our established model of progressive CKD (the Cy/+ rat), pharmacological and non- pharmacological interventions. We will assess mitochondrial function using high resolution respirometry, aerobic capacity via VO2max assessment, muscle strength and fatigue assessed by electrical stimulation and maximal voluntary grip strength, muscle mass, and overall physical activity levels. The interdisciplinary mentoring team and I are perfectly positioned to undertake this translational work based on our clinical and preclinical expertise in CKD, myostatin and skeletal muscle.
In aim 1 we will assess the efficacy of moderate and high intensity AEROBIC exercise in improving skeletal muscle metabolism and aerobic capacity in CKD rats.
In aim 2, we will assess the efficacy of moderate and high intensity RESISTANCE training on skeletal muscle size and strength in CKD rats.
In aim 3 we will assess the efficacy of myostatin blocking therapy compared to optimal exercise in increasing muscle mass, muscle metabolism and function. The current proposal will develop a number of skills required to be a successful, independent translational research. While my long term goal is patient implementation, building a solid basic science skill set will allow for parallel studies that provide a mechanistic understanding. If these studies show efficacy in benefiting skeletal muscle function and/or mass, these treatments could be rapidly translated into the clinical setting.

Public Health Relevance

Patients with advanced chronic kidney disease have a marked loss and dysfunction of skeletal muscle which leads to increased falls, morbidity and mortality. The mechanisms of skeletal muscle loss and dysfunction in chronic kidney disease are not clear. In the present study we will examine if aerobic exercise, resistance exercise, and/or myostatin blocking therapy can improve skeletal muscle metabolism, size and strength in CKD rats.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK110429-02
Application #
9334217
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK-B)
Program Officer
Rankin, Tracy L
Project Start
2016-08-18
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$130,627
Indirect Cost
$9,676
Name
Indiana University-Purdue University at Indianapolis
Department
Other Health Professions
Type
Schools of Allied Health Profes
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Avin, Keith G; Vallejo, Julian A; Chen, Neal X et al. (2018) Fibroblast growth factor 23 does not directly influence skeletal muscle cell proliferation and differentiation or ex vivo muscle contractility. Am J Physiol Endocrinol Metab 315:E594-E604
Moorthi, Ranjani N; Avin, Keith G (2017) Clinical relevance of sarcopenia in chronic kidney disease. Curr Opin Nephrol Hypertens 26:219-228
Salazar, Tatiana E; Richardson, Matthew R; Beli, Eleni et al. (2017) Electroacupuncture Promotes Central Nervous System-Dependent Release of Mesenchymal Stem Cells. Stem Cells 35:1303-1315
Avin, Keith G; Chen, Neal X; Organ, Jason M et al. (2016) Skeletal Muscle Regeneration and Oxidative Stress Are Altered in Chronic Kidney Disease. PLoS One 11:e0159411