Acute Nutritional Deprivation: Diaphragm Influences

Summary

Principal Investigator: MICHAEL IAN LEWIS
Abstract: The overall objective is to develop a mechanistic approach and improved understanding of potential molecular targets in the management of disordered protein turnover and muscle atrophy in the diaphragm of a clinically relevant animal model of severe short-term nutritional deprivation (ND). Hypothesis 1: Down-regulation of the PI3K/Akt/mTOR signal transduction pathway is an important determinant of disordered synthesis of muscle proteins and atrophy with ND. Reduced IGF-1 levels are a major signal responsible for this down-regulation. Stimulation of PI3K/Akt/mTOR signal transduction pathway by administration of IGF-1 will augment the synthesis of muscle proteins by enhancing signal transduction pathways mediating translation initiation with attenuation of muscle atrophy. Aim 1: We propose to measure in a time series (i.e., days 1 & 4) in severe ND, the phosphorylation of Akt and Ser2448,an important regulatory domain in mTOR, together with downstream targets important in translation initiation of muscle proteins (i.e., phosphorylation states of 4E-BPI and p70S6K) and the phosphorylation of ERK1/2 and GSK3, 2 other pathways through which IGF-1 could act. The above will be measured with and without the infusion of IGF-1 and correlated with 1) muscle protein synthesis and degradation including an analysis of the turnover of specific protein pools (MHC, sarcoplasmic, mitochondrial); 2) diaphragm mass and fiber size; and 3) diaphragm specific force. Hypothesis 2: The impact of rapamycin, an inhibitor of mTOR, on IGF-1 rescue in the ND model is unknown. Possibilities include marked attenuation of the beneficial effect of IGF-1 or maintained rescue due to activation of alternate pathways. Aim 2: We propose to administer rapamycin to ND animals infused with IGF-I and to measure the key proteins mediating IGF-1 signal transduction pathways together with outcome measures as outlined in aim #1. Hypothesis 3: Enhanced muscle protein degradation with severe ND is mediated in large part by activation of the ubiquitin-proteasome pathway. While IGF-1 infusion may potentially attenuate muscle protein breakdown with ND, the addition of an inhibitor of the ubiquitin proteasome mediated proteolysis (eicosapentaenoic acid; EPA) to IGF-1 infusion will further attenuate or reverse muscle fiber atrophy. The provision of EPA alone to ND animals will determine the relative importance of muscle proteolysis to disordered turnover in this model. Aim 3: We propose to administer EPA with and without IGF-1 infusion to ND animals. We will evaluate gene and protein expression of key components of the ubiquitin-proteasome pathway. These will include: the newly described muscle specific E3 ligases (MuRF1 and MAFbx), key enzymes mediating the N-end rule pathway (E2-I4k and E3alpha ), polyubiquitin, proteasome subunits (C2 & C8) and ubiquitin conjugated protein content. The above will be correlated with outcome measures as outlined in aim #1. Hypothesis 4: Increased endogenous corticosteroid (CS) production is present with severe ND, which contributes to muscle fiber atrophy by suppressing muscle protein synthesis and enhancing degradation through the ubiquitin-proteasome pathways. Suppression of CS effects by administration of a CS receptor blocker (RU38486) will reverse CS induced effects on muscle protein turnover and enable one to evaluate the contribution of endogenous CS to fiber atrophy. Aim 4: We propose to administer RU38486 to animals subjected to severe short-term ND. We will evaluate gene and protein expression of key components of the ubiquitin-proteasome pathway, as outlined in aim #3, as well as markers of signal transduction and outcome measures as outlines in aim #1.
Funding Period: 2004-04-01 - 2009-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Testosterone and resistance training effects on muscle nitric oxide synthase isoforms in COPD men
    Bahman Chavoshan
    Rehabilitation Clinical Trials Center, Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA 90502, USA
    Respir Med 106:269-75. 2012
  2. pmc Metabolic and morphometric profile of muscle fibers in chronic hemodialysis patients
    Michael I Lewis
    Division of Pulmonary Critical Care Medicine, Burns and Allen Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
    J Appl Physiol (1985) 112:72-8. 2012
  3. ncbi Effects of malnutrition with or without eicosapentaenoic acid on proteolytic pathways in diaphragm
    Joanne M Bando
    Division of Pulmonary Critical Care Medicine, The Burns and Allen Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States
    Respir Physiol Neurobiol 180:14-24. 2012
  4. ncbi Tumor necrosis factor-alpha and malnutrition-induced inhibition of diaphragm fiber growth in young rats
    Michael I Lewis
    Division of Pulmonary Critical Care Medicine, The Burns and Allen Research Institute, Cedars Sinai Medical Center, 8700 Beverly Blvd, Rm 6732, Los Angeles, CA 90048, USA
    J Appl Physiol (1985) 99:1649-57. 2005
  5. ncbi Effect of severe short-term malnutrition on diaphragm muscle signal transduction pathways influencing protein turnover
    Michael I Lewis
    Division of Pulmonary Critical Care Medicine, Burns and Allen Research Institute, Cedars Sinai Medical Center, 8700 Beverly Blvd, Rm 6732, Los Angeles, CA 90048, USA
    J Appl Physiol (1985) 100:1799-806. 2006
  6. ncbi Skeletal muscle adaptations to testosterone and resistance training in men with COPD
    Michael I Lewis
    Division of Pulmonary and Critical Care Medicine, The Burns and Allen Research Institute at Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
    J Appl Physiol (1985) 103:1299-310. 2007
  7. pmc Time course expression of Foxo transcription factors in skeletal muscle following corticosteroid administration
    John E Cho
    Division of Pulmonary Critical Care Medicine, The Burns and Allen Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
    J Appl Physiol (1985) 108:137-45. 2010

Scientific Experts

  • Michael I Lewis
  • Xiaoyu Da
  • Mario Fournier
  • Bahman Chavoshan
  • Joanne M Bando
  • John E Cho
  • Mehdi Rambod
  • Richard Casaburi
  • Thomas W Storer
  • Janos Porszasz

Detail Information

Publications7

  1. ncbi Testosterone and resistance training effects on muscle nitric oxide synthase isoforms in COPD men
    Bahman Chavoshan
    Rehabilitation Clinical Trials Center, Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, CA 90502, USA
    Respir Med 106:269-75. 2012
    ..We hypothesized that resistance exercise training (R) and/or testosterone supplementation (T) would alter the transcription and expression of the NOS isoenzymes in COPD skeletal muscle...
  2. pmc Metabolic and morphometric profile of muscle fibers in chronic hemodialysis patients
    Michael I Lewis
    Division of Pulmonary Critical Care Medicine, Burns and Allen Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
    J Appl Physiol (1985) 112:72-8. 2012
    ..The enlarged CSA of muscle fibers may, in part, be accounted for by edema. We speculate that these changes contribute to reduce limb strength in MHD patients by reducing specific force...
  3. ncbi Effects of malnutrition with or without eicosapentaenoic acid on proteolytic pathways in diaphragm
    Joanne M Bando
    Division of Pulmonary Critical Care Medicine, The Burns and Allen Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States
    Respir Physiol Neurobiol 180:14-24. 2012
    ..Our study provides unique data on proteolytic signals with ND and has important implications for future studies using EPA...
  4. ncbi Tumor necrosis factor-alpha and malnutrition-induced inhibition of diaphragm fiber growth in young rats
    Michael I Lewis
    Division of Pulmonary Critical Care Medicine, The Burns and Allen Research Institute, Cedars Sinai Medical Center, 8700 Beverly Blvd, Rm 6732, Los Angeles, CA 90048, USA
    J Appl Physiol (1985) 99:1649-57. 2005
    ..Thus rat anti-TNF-alpha at a dose known to neutralize the cytokine failed to attenuate or reverse ND-induced inhibition of DIA fiber growth in our model...
  5. ncbi Effect of severe short-term malnutrition on diaphragm muscle signal transduction pathways influencing protein turnover
    Michael I Lewis
    Division of Pulmonary Critical Care Medicine, Burns and Allen Research Institute, Cedars Sinai Medical Center, 8700 Beverly Blvd, Rm 6732, Los Angeles, CA 90048, USA
    J Appl Physiol (1985) 100:1799-806. 2006
    ..This forms the framework for future studies aimed at identifying therapeutic targets in the management of short-term nutritionally induced cachectic states...
  6. ncbi Skeletal muscle adaptations to testosterone and resistance training in men with COPD
    Michael I Lewis
    Division of Pulmonary and Critical Care Medicine, The Burns and Allen Research Institute at Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
    J Appl Physiol (1985) 103:1299-310. 2007
    ..Our data suggest that the combined interventions produced an enhanced local anabolic milieu driven in large part by the muscle IGF system, despite potentially negative biochemical influences present in COPD patients...
  7. pmc Time course expression of Foxo transcription factors in skeletal muscle following corticosteroid administration
    John E Cho
    Division of Pulmonary Critical Care Medicine, The Burns and Allen Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
    J Appl Physiol (1985) 108:137-45. 2010
    ..Elucidating the dynamic catabolic responses to CS challenge is important in understanding the mechanisms underlying muscle atrophy and therapeutic measures to offset this...