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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Wang, Yan Z
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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Huffman, Kim M; Jessee, Ryan; Andonian, Brian et al. (2017) Molecular alterations in skeletal muscle in rheumatoid arthritis are related to disease activity, physical inactivity, and disability. Arthritis Res Ther 19:12
AbouAssi, Hiba; Connelly, Margery A; Bateman, Lori A et al. (2017) Does a lack of physical activity explain the rheumatoid arthritis lipid profile? Lipids Health Dis 16:39
Bartlett, David B; Connelly, Margery A; AbouAssi, Hiba et al. (2016) A novel inflammatory biomarker, GlycA, associates with disease activity in rheumatoid arthritis and cardio-metabolic risk in BMI-matched controls. Arthritis Res Ther 18:86
Barberio, Matthew D; Huffman, Kim M; Giri, Mamta et al. (2016) Pyruvate Dehydrogenase Phosphatase Regulatory Gene Expression Correlates with Exercise Training Insulin Sensitivity Changes. Med Sci Sports Exerc 48:2387-2397
Barberio, Matthew D; Huffman, Kim M; Giri, Mamta et al. (2016) PDPR Gene Expression Correlates with Exercise-Training Insulin Sensitivity Changes. Med Sci Sports Exerc :
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
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; 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
Huffman, Kim M; Hawk, Victoria H; Henes, Sarah T et al. (2012) Exercise effects on lipids in persons with varying dietary patterns-does diet matter if they exercise? Responses in Studies of a Targeted Risk Reduction Intervention through Defined Exercise I. Am Heart J 164:117-24

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