Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease, with a prevalence of 1% worldwide. Nearly two-thirds of RA patients suffer from loss of skeletal muscle mass, which often co-occurs with central obesity, a feature of metabolic syndrome [2]. Lower muscle mass leads to muscle weakness, a major contributor of physical impairment in patients with RA, even after multivariate adjustment for demographic and disease variables. My broad long-range goal is to understand at a mechanistic level the metabolic and physiologic abnormalities of skeletal muscle in patients with RA; and to use that knowledge to improve therapy for skeletal muscle dysfunction in RA. As a first step to achieve that goal, I hypothesize that increased lipid content in skeletal muscle contributes to insulin resistance and impaired skeletal muscle homeostasis and function in RA. I further hypothesize that treatment with pioglitazone will improve muscle function by decreasing lipid deposition in skeletal muscle, restoring the anabolic effects of insulin and attenuating inflammation. In order to test these hypotheses, I will establish a cohort of well-characterized RA subjects and non-RA controls, who will undergo assessment of physical function, body composition, disease activity, and needle biopsy from the vastus lateralis muscle (aim 1).
In aim 2, I will conduct a 12-week, double-blind, and placebo- controlled study with pioglitazone in patients with RA who are insulin resistant to determine whether treatment of insulin resistance will improve functional characteristics, cellular and molecular responses in their skeletal muscle. Completion of the proposed research will begin to define the molecular underpinnings of impaired skeletal muscle homeostasis in RA. I will use the information gained from this cohort to design clinical interventions in this patient population to prevent and/or treat skeletal muscle dysfunction in RA. Ultimately, this work promises to provide novel targets to treat and prevent a devastating complication of RA.

Public Health Relevance

In Rheumatoid arthritis (RA), nearly two-thirds of patients suffer from loss of skeletal muscle mass; and muscle weakness is a major contributor to physical impairment. Insulin resistance is implicated in the loss of muscle mass in type 2 diabetes and aging, but in patients with RA, the degree with which insulin resistance and associated lipid deposition in skeletal muscle contribute to muscle dysfunction is not known. The goals of this project are to determine the effects of insulin resistance and associated lipid deposition on RA skeletal muscle; and to elucidated if pioglitazone therapy, directed at insulin resistance and lipid deposition in skeletal muscle, can improve muscle dysfunction in patients with RA.

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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Special Emphasis Panel (ZAR1-YL (M1))
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Witter, James
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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Hanaoka, Beatriz Y; Ithurburn, Matthew P; Rigsbee, Cody A et al. (2018) Chronic Inflammation in Rheumatoid Arthritis and Mediators of Skeletal Muscle Pathology and Physical Impairment: A Review. Arthritis Care Res (Hoboken) :
Hanaoka, Beatriz Y; Ormseth, Michelle J; Michael Stein, C et al. (2018) Secretory sphingomyelinase (S-SMase) activity is elevated in patients with rheumatoid arthritis. Clin Rheumatol 37:1395-1399
Dragoljevic, Dragana; Kraakman, Michael J; Nagareddy, Prabhakara R et al. (2018) Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis. Eur Heart J 39:2158-2167