diet, exercise, nsaids, and inclusion body myositis€¦ · diet, exercise, nsaids, and inclusion...

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Diet, Exercise, NSAIDs, and Inclusion Body Myositis M. Paul Murphy Associate Professor Molecular and Cellular Biochemistry & Sanders-Brown Center on Aging University of Kentucky

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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