Quadriceps muscle strength loss contributes directly to the pain, disability and morbidity associated with knee osteoarthritis (OA). Strength loss of up to 40% typically occurs and may actually precede the development of knee OA. Intriguing evidence suggests that OA-associated quadriceps weakness may be the result of altered muscle quality, and that muscle weakness may actually precede the development of OA. We hypothesize that changes in the muscle environment, including inflammatory cell infiltration, fibrosis, fat infiltration, and changes in stem cell activity contribute to muscle weakness associated with OA. Testing this hypothesis is a natural extension of the parent grant which seeks to assess the effect of strengthening programs on quadriceps strength, pain, disability, and joint loading. The BIRT application will bring together for the first time experts in the areas of muscle biology and joint biology/biomechanics to assess the adaptations within muscle that may contribute to the strength loss seen in those suffering with knee OA. Muscle biopsies from the vastus lateralis of control healthy subjects and patients with knee OA will be assessed for muscle fiber morphology, size and type, as well as markers of immune cell infiltration. Muscle stem cell (satellite cell) abundance and the abundance of other progenitor populations will be quantified to identify changes that may limit muscle adaptability. These properties will be compared to the strength measures and cross sectional area of the muscle to determine their relationship. We propose two specific aims:
in Aim 1 we hypothesize that knee OA is associated with neutrophil and pro-inflammatory macrophage infiltration in the quadriceps muscle.
In Aim 2 we hypothesize that knee OA is associated with alterations in muscle progenitor populations resulting in fat accumulation and fibrosis, at the expense of muscle repair, maintenance, and growth. To accomplish these aims this BIRT application brings together Drs. Messier and Loeser from the parent grant at Wake Forest University with Drs. Peterson and Noehren at the University of Kentucky. We propose to take 20 muscle biopsies from patients at baseline from the parent grant and compare them to age-, sex-, race-, activity-, and BMI-matched healthy control subjects who have no radiographic or symptomatic history of knee OA. Immunohistochemcial analyses will characterize the muscle environment. These data will greatly accelerate the development of subsequent grants among the research team assessing characteristics of responders and non-responders to exercise, optimal exercise prescription to target the identified adaptations, and identify those early in the disease process who might be most at risk for strength loss.
Given the prevalence and impact of osteoarthritis and the clinically significant reduction in strength in people afflicted with this disabling disease, identifying the underlying cellular and myofiber adaptations that contribute to the loss of strengt is essential to develop optimal treatment interventions that target the underlying source of the weakness.
|Messier, S P; Callahan, L F; Golightly, Y M et al. (2015) OARSI Clinical Trials Recommendations: Design and conduct of clinical trials of lifestyle diet and exercise interventions for osteoarthritis. Osteoarthritis Cartilage 23:787-97|
|Messier, Stephen P; Beavers, Daniel P; Loeser, Richard F et al. (2014) Knee joint loading in knee osteoarthritis: influence of abdominal and thigh fat. Med Sci Sports Exerc 46:1677-83|
|Messier, Stephen P; Mihalko, Shannon L; Beavers, Daniel P et al. (2013) Strength Training for Arthritis Trial (START): design and rationale. BMC Musculoskelet Disord 14:208|