Persons with rheumatoid arthritis (RA) are at increased risk of cardiovascular (CV) disease and insulin resistance, a metabolic CV risk factor. In individuals without RA, habitual physical activity improves insulin action and CV morbidity. The potential for exercise to confer similar health benefits in RA patients has not been explored. This proposal outlines a career training and research plan that will provide the basis for developing specific interventions whereby physical activity can be used to modulate metabolic CV risk in RA. The career development plan focuses on building a translational research program that applies state-of-the-art technology to perform mechanistic studies in human populations. The objectives of this plan are as follows: 1) To develop training and skills relevant to metabolism;2) To perform and gain proficiency in skeletal muscle biopsy techniques;3) To develop expertise in exercise physiology and physical activity interventions;4) To develop skills in clinical trial design and implementation and obtain training in the responsible conduct of research;5) To develop advanced skills in statistical analysis;and 6) To advance skills in manuscript preparation and grant writing. We hypothesize that RA-associated inflammation and inactivity mediate skeletal muscle atrophy and increased abdominal obesity, which in turn lead to mitochondrial dysfunction and eventual insulin resistance. These hypotheses will be tested via the following specific aims: 1) To determine whether persons with RA have altered body composition and increased lipolysis compared with sex-, age- and BMI-matched controls;2) To determine whether RA associates with heightened activation of signaling pathways involved in muscle wasting and coincident changes in muscle fiber composition;3) To determine whether intramuscular lipid imbalance and/or mitochondrial dysfunction in persons with RA contributes to impaired insulin signaling;and, 4) To determine whether persons with RA are insulin resistant, relative to sex-, age- and BMI-matched controls, and to evaluate predictors of insulin sensitivity in RA patients, including body composition, lipolysis, and activation of signaling pathways implicated in muscle wasting and insulin desensitization. Thus, this work will explore innovative hypotheses applicable to a non-pharmacologic treatment approach to RA, and implement a comprehensive research program that seeks to deepen our understanding of the mechanisms of human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AR054904-05
Application #
8319616
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Wang, Yan Z
Project Start
2008-09-05
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$72,323
Indirect Cost
$4,869
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Huffman, K M; Pieper, C F; Hall, K S et al. (2015) Self-efficacy for exercise, more than disease-related factors, is associated with objectively assessed exercise time and sedentary behaviour in rheumatoid arthritis. Scand J Rheumatol 44:106-10
Huffman, Kim M; Koves, Timothy R; Hubal, Monica J et al. (2014) Metabolite signatures of exercise training in human skeletal muscle relate to mitochondrial remodelling and cardiometabolic fitness. Diabetologia 57:2282-95
Huffman, Kim M; Sun, Jie-Lena; Thomas, Laine et al. (2014) Impact of baseline physical activity and diet behavior on metabolic syndrome in a pharmaceutical trial: results from NAVIGATOR. Metabolism 63:554-61
AbouAssi, Hiba; Tune, K Noelle; Gilmore, Brian et al. (2014) Adipose depots, not disease-related factors, account for skeletal muscle insulin sensitivity in established and treated rheumatoid arthritis. J Rheumatol 41:1974-9
Huffman, Kim M; Redman, Leanne M; Landerman, Lawrence R et al. (2012) Caloric restriction alters the metabolic response to a mixed-meal: results from a randomized, controlled trial. PLoS One 7:e28190
Redman, Leanne M; Huffman, Kim M; Landerman, Lawrence R et al. (2011) Effect of caloric restriction with and without exercise on metabolic intermediates in nonobese men and women. J Clin Endocrinol Metab 96:E312-21
Huffman, Kim M; Pieper, Carl F; Kraus, Virginia B et al. (2011) Relations of a marker of endothelial activation (s-VCAM) to function and mortality in community-dwelling older adults. J Gerontol A Biol Sci Med Sci 66:1369-75
Huffman, Kim M; Slentz, Cris A; Kraus, William E (2011) Control arms in exercise training studies: transitioning from an era of intervention efficacy to one of comparative clinical effectiveness research. J Appl Physiol (1985) 111:946-8
Huffman, Kim M; Slentz, Cris A; Bateman, Lori A et al. (2011) Exercise-induced changes in metabolic intermediates, hormones, and inflammatory markers associated with improvements in insulin sensitivity. Diabetes Care 34:174-6
Huffman, K M; Hall, K S; Sloane, R et al. (2010) Is diabetes associated with poorer self-efficacy and motivation for physical activity in older adults with arthritis? Scand J Rheumatol 39:380-6

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