Calcineurin signaling, PGC-1 alpha and protein-energy wasting in kidney disease

Summary

Principal Investigator: S Russ Price
Abstract: DESCRIPTION (provided by applicant): Protein-energy wasting contributes to the weakness and fatigue that is frequently seen in patients with chronic kidney disease (CKD). Despite significant advances in understanding the mechanisms causing the loss of lean body mass and protein reserves, attempts to develop pharmaceutical interventions to attenuate wasting have been unsuccessful. In contrast, exercise can reduce proteolysis and preserve lean body mass in CKD although how its effects are achieved remains poorly understood. We and others have reported that the level of the transcription coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) is decreased during CKD and other cachexia-inducing conditions. This is notable because PGC-1a expression in normal muscle is increased by exercise and transgenic overexpression of PGC-1a protects against muscle loss. PGC-1a is a critical "master regulator" that integrates energy and protein metabolism. It functions by promoting mitochondrial biogenesis and attenuating the activity of important transcription factors like FOXO which upregulate proteolytic system genes. Understanding how exercise decreases wasting in CKD will improve our ability to treat fatigue and weakness in patients. To accomplish this goal, we must first understand the biochemical basis for dysregulation of PGC1a during CKD-induced wasting. This project will test the hypothesis that the reduction in PGC-1a expression during CKD and glucocorticoid-related wasting results from abnormal signaling through one or more pathways that are regulated by calcineurin (Cn), a calcium-activated serine/threonine phosphatase. We will examine the myocyte enhancer factor 2 (MEF2)/cytoplasmic nuclear factor of activated T cells (NFATc) pathways because both transcription factors are Cn substrates that regulate PGC-1a transcription in muscle cells. The third pathway to be studied is the Transducer of Regulated CREB 1 (TORC1)/ cyclic AMP-responsive element-binding protein (CREB) pathway. TORC1 is a Cn-activated transcription coactivator of CREB that is required for PGC-1a expression. Our preliminary evidence suggests that TORC1 function is impaired during cachexia. Once the mechanisms of PGC-1a dysregulation are characterized, we will test whether exercise improves Cn signaling in CKD mice, thus leading to increased expression or PGC-1a, decreased protein degradation, and improvement in strength. The long-term goal of our research is to improve the treatment and rehabilitation of CKD patients, perhaps through the development of new exercise mimetic therapies. Given the similarities of the wasting syndromes in a broad range of debilitating diseases (e.g., cancer, diabetes, heart disease), our findings may be widely applicable to many patients.
Funding Period: 2012-04-15 - 2016-03-31
more information: NIH RePORT

Top Publications

  1. pmc Nutritional intervention restores muscle but not kidney phenotypes in adult calcineurin Aα null mice
    Kirsten Madsen
    Department of Medicine Division of Nephrology, Emory University School of Medicine, Atlanta, Georgia, United States of America
    PLoS ONE 8:e62503. 2013
  2. pmc Calcineurin: a poorly understood regulator of muscle mass
    Matthew B Hudson
    Department of Medicine, Renal Division, Emory University School of Medicine, Atlanta, GA 30322, United States
    Int J Biochem Cell Biol 45:2173-8. 2013
  3. pmc miR-23a is decreased during muscle atrophy by a mechanism that includes calcineurin signaling and exosome-mediated export
    Matthew B Hudson
    Renal Division, Department of Medicine, Emory University, Atlanta, Georgia
    Am J Physiol Cell Physiol 306:C551-8. 2014
  4. pmc Docosahexaenoic acid prevents palmitate-induced activation of proteolytic systems in C2C12 myotubes
    Myra E Woodworth-Hobbs
    Nutrition and Health Sciences Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA, USA Department of Medicine, Renal Division, Emory University, Atlanta, GA, USA Electronic address
    J Nutr Biochem 25:868-74. 2014

Detail Information

Publications4

  1. pmc Nutritional intervention restores muscle but not kidney phenotypes in adult calcineurin Aα null mice
    Kirsten Madsen
    Department of Medicine Division of Nephrology, Emory University School of Medicine, Atlanta, Georgia, United States of America
    PLoS ONE 8:e62503. 2013
    ..This study illustrates the importance of re-examining the phenotypes of CnAα-/- mice and the advances that are now possible with the use of adult, rescued knockout animals...
  2. pmc Calcineurin: a poorly understood regulator of muscle mass
    Matthew B Hudson
    Department of Medicine, Renal Division, Emory University School of Medicine, Atlanta, GA 30322, United States
    Int J Biochem Cell Biol 45:2173-8. 2013
    ..This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. ..
  3. pmc miR-23a is decreased during muscle atrophy by a mechanism that includes calcineurin signaling and exosome-mediated export
    Matthew B Hudson
    Renal Division, Department of Medicine, Emory University, Atlanta, Georgia
    Am J Physiol Cell Physiol 306:C551-8. 2014
    ..Dex did not alter the number of exosomes released into the media. We conclude that atrophy-inducing conditions downregulate miR-23a in muscle by mechanisms involving attenuated Cn/NFAT signaling and selective packaging into exosomes. ..
  4. pmc Docosahexaenoic acid prevents palmitate-induced activation of proteolytic systems in C2C12 myotubes
    Myra E Woodworth-Hobbs
    Nutrition and Health Sciences Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA, USA Department of Medicine, Renal Division, Emory University, Atlanta, GA, USA Electronic address
    J Nutr Biochem 25:868-74. 2014
    ..These data indicate that palmitate induces myotube atrophy, at least in part, by activating multiple proteolytic systems and that DHA counters the catabolic effects of palmitate by restoring Akt/FoxO signaling. ..

Research Grants30

  1. Dysfunctional PGC-1alpha expression in skeletal muscle during diabetes
    S Russ Price; Fiscal Year: 2013
    ..Use of Cn inhibitors could have a negative impact on both types of patients. Lastly, our results could be broadly applicable to Veterans suffering from many types of debilitating diseases associated with atrophy. ..
  2. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  3. Mechanisms of action of ghrelin in muscle and adipose tissue in cancer-related ca
    Jose M Garcia; Fiscal Year: 2013
    ..Cachexia is also a complication of many other conditions including lung and heart disease and aging, the knowledge generated through this proposal also will help us in establishing new therapies for these conditions. ..
  4. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  5. PROTEIN NUTRITION IN EXPERIMENTAL UREMIA
    WILLIAM EVANS MITCH; Fiscal Year: 2013
    ..The significance of our results is that the two-hit model could apply to many conditions because GC and decreased insulin responses are present in many catabolic illnesses, ..
  6. Nutrition and Anabolic Interventions in Cancer Cachexia
    Melinda Sheffield-Moore; Fiscal Year: 2013
    ..Results from this study may lead to better ways of preventing cancer-related weight loss, and improve the quality of life and survival of those affected by cervical cancer. ..
  7. Role of Ca2+/calmodulin kinases in skeletal muscle glucose transport and growth.
    CAROL WITCZAK; Fiscal Year: 2013
    ..Thus, in this application, we propose to investigate the role of CaMKKalpha in the regulation of growth, protein synthesis and mTOR signaling in skeletal muscle. ..
  8. Regulation of Nutrient Sensing and Muscle Wasting by Alcohol
    Charles H Lang; Fiscal Year: 2013
    ....
  9. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013
    ..Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years. ..