Diet, Exercise, NSAIDs, and Inclusion Body Myositis Diet, Exercise, NSAIDs, and Inclusion Body...

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Transcript of Diet, Exercise, NSAIDs, and Inclusion Body Myositis Diet, Exercise, NSAIDs, and Inclusion Body...

  • Diet, Exercise, NSAIDs, and

    Inclusion Body Myositis

    M. Paul Murphy

    Associate Professor

    Molecular and Cellular Biochemistry

    & Sanders-Brown Center on Aging

    University of Kentucky

  • What is AD?

  • Amyloid Precursor Protein and β-Amyloid

    Extracellular

    Intracellular

    APP

    α-secretase

    β-secretase

    γ-secretase

    sAPP-α

    C83

    Aβ region

    sAPP-β

    Constitutive Processing (~90%) Amyloidogenic Processing (~10%)

    AICD

    Adam Weidner

  • Is AD a loss of Repression on the A Producing Enzymes?

    Normal Aging

    -Secretase

    -Secretase

    -Secretase

    -Secretase

    A

    Pathologic Aging

    Healthy Brain Alzheimer’s Disease

  • Amyloid Pathology is Generic

    Adapted from: Forman et. al., Nature Medicine, 10: 1055-63, 2004

    AD (Plaque) FTD (Tangle) PD (Lewy Body)

    ALS (Cytoplasm Inclusion) HD (Nuclear Inclusion) CJD (PrPres Plaques)

  • IBM and AD

    • In the brain of AD

    patients the A forms

    plaques that are

    outside of the cells

    • In the muscle of IBM patients the A forms inclusions that are inside of the cells

    A

    A (in green)

  • Connection…?

    1) A -positive, non-congophilic deposits appear prior to frank vacuolization in IBM affected muscle fibers

    2) mRNA for APP, the larger protein from which A is derived, is increased in sIBM, as is the APP protein itself

    -secretase, a major amyloidogenic enzyme involved in AD, is up regulated in IBM (as well as in AD and aging in general)

    4) Overexpression of APP and/or APP fragments containing A in the muscle of transgenic mice leads to degenerative changes similar to the disease state in humans

  • IBM Mouse Models • One of the only options to

    resolve the actual role of A in the disease process, is to perform experiments in animal models.

    • IBM-T7A6 mouse: reported in 2002 in collaboration with Frank LaFerla, UCI

    • Overexpresses full length APP in muscle under the direction of a creatine kinase promoter

  • What is

    sIBM?

    NSAIDs

    APP Transgenic

    APP Knock-In

    ?

    ? Lifestyle

    Interventions

    Pharmacology and

    Genetics

    Exercise

    Diet

  • Exercise

    • Nice resonance for a muscle disease

    • Several anecdotal reports indicate that moderate exercise may help IBM patients

    • Simple running wheel activity reduces pathology in several mouse models of AD

    • However, minimal effect in sIBM mice

  • Diet

    Genotype

    Wild-type APP PS1 APP/PS1

    control KD control KD control KD control KD

    Weight (g) Baseline 25±3 24±3 23±1 23±1 27±2 25±2 25±1 25±1

    1 montha 28±2 25±2 28±1 25±1 31±2 25±2 29±1 27±1

    Ketones (mM) Baseline 0.37±0.07 0.3±0.06 0.36±0.02 0.48±0.09 0.46±0.07 0.44±0.10 0.37±0.03 0.42±0.04

    1 montha 0.37±0.22 1.0±0.22 0.36±0.10 1.09±0.10 0.34±0.17 0.98±0.17 0.36±0.12 1.18±0.12

    Glucose

    (mg/dL)

    Baseline 143±28 133±4 140±7 151±9 126±15 142±22 140±10 125±9

    1 month 89±13 106±13 104±6 111±6 98±10 91±10 109±7 115±7

    Insulin (ng/mL) a 1.74±0.37 0.42±0.37 1.82±0.17 0.52±0.17 1.88±0.29 0.64±0.29 2.13±0.20 0.71±0.20

    Mice do get a little better in muscle function, but

    NO effect on the underlying pathology

  • NSAIDs

  • Other Mice?

  • APP A Inflam. Weak?

    C57 Mice Yes

    B6C3

    Mice - No Knock-In

    Mice - No NSAIDs

    (+) - No Effect NSAIDs

    (-) - - No Effect

    Diet - - - Improve

    P

    PP PP P

    PP

    P P

    P

    P

    P

  • NIH (R01 NS058382, P20 RR020171, P01

    AG005119, P30 AG005144, T32

    HL086341), KSEF, NSF, AFAR, CART

    Foundation, The Myositis Association, The

    Alzheimer’s Association, and The American

    Heart Association

    Rachel Ahmed, Grad Student

    Kristen Kingry, Research Assistant

    Robin Webb, Grad Student

    Angela Spinelli, Research Assistant

    Chris Holler, Grad Student

    Feng Li, Research Technician

    Katharina Kohler, Research Technician

    Moshe Khurgel, Visiting Scientist

    Tina Beckett, Research Analyst

    Dana Niedowicz, Post-Doc

    Thomas Platt, Grad Student

    Adam Weidner, Post-Doc

    Christa Studzinski, Post-Doc

    Murphy

    Lab, Barcel ona 2011