Mechanistic Approach to Preventing Atrophy and Restoring Function in Older Adults

The investigative team has completed recent studies showing that essential amino acid (EAA) supplementation attenuates quadriceps atrophy and accelerates the return of functional mobility following TKA. For patients on EAA, quadriceps atrophy was only -6% and -3% in the operative and non-operative quadriceps, respectively, 6 wks after TKA, but -18% and -10%, respectively, in patients on Placebo, a threefold difference. Of clinical relevance, the patients on EAA were able to maintain strength and demonstrated an accelerated return of functional mobility vs. Placebo 6 wks post-TKA. Positive changes at the cellular level are likely responsible for the reduction in muscle loss and preservation of strength, and to explain the acceleration of the return of functional mobility. As such, we hypothesize that twice-daily ingestion of 23 g of EAA from 1 wk before to 6 wks after TKA will increase basal rates of muscle protein synthesis via inactivation of catabolic signaling (FoxO3a), and up-regulation of anabolic and cyto-protective proteins. We also propose that short-term atrophy prevention and accelerated return of functional mobility will translate into long-term (6 mo and 1 yr post-TKA) structural and functional adaptations, leading to improved quality of life in TKA patients with EAA supplementation vs. Placebo.

The study will use a two-arm parallel design to determine the effect of EAA supplementation on post-TKA muscle cell structure and function, and quality of life in the shorter term (6 months post-TKA) and long term (1 yr post-TKA) vs. Placebo. Subjects will be 80 older male and female adults having primary TKA at the Slocum Center for Orthopedics and Sports Medicine, Eugene, Oregon. Slocum study staff will pre-screen/identify potential subjects for recruitment based on inclusion/exclusion criteria. Eligible patients will be invited to join the study. After the completion of informed consent procedures, participants will be assigned a unique patient identification number, and randomly assigned to either EAA or Placebo on a 1:1 allocation ratio, with blinding of treatment condition to subject and research staff/statisticians collecting data. Twice-daily ingestion of 23 g of supplement will begin 7 days prior to TKA and end at 6 wks post. EAA subjects will receive EAA and Placebo subjects will receive the non-essential amino acid Alinine. Subjects will document compliance with the supplement protocol in a log book and will return empty vials. Subjects will be followed for 1 yr.

Key research questions are: (a) Does EAA prevent shorter-term (6 wks post-TKA) bilateral muscle atrophy, preserve quadriceps strength, and accelerate the return of functional mobility vs. Placebo? (b) Are there shorter-term sex differences on outcome measures? (c) Will EAA increase longer-term (6 mo post-TKA) quadriceps strength and functional mobility vs. Placebo? (d) Does EAA improve long-term (1 yr post-TKA) functional mobility and measures of quality of life vs. Placebo? (e) Are there long-term sex differences in functional mobility or measures of quality of life? Assessment points will be at 6 wks, 4 wks, and 1 wk prior to surgery, and 1 wk, 2 wks, 6 wks, 6 mos, and 1 yr post-TKA. At different assessment points, we will collect demographic, medical (e.g., length of hospital stay, tourniquet use), physiological (e.g., muscle biopsy, MRI, DEXA, strength; blood tests), pharmacologic, functional mobility, physical activity (accelerometer), psychometric (e.g., quality of life; Veterans RAND 12-item Health Survey [VR-12]), food intake (3-day diary), physical therapy, and perceived pain data. The following schedule of assessments will be followed: no more than 6 mo pre-TKA (enrollment and screening), 6 wks pre-TKA (screening, surveys, DEXA scan, MRI test, physical activity and food recording), 4 weeks pre-TKA (blood draw, strength and functional mobility testing, muscle and fat biopsy); 1 wk pre-TKA and in hospital (physical activity and food recording); 1 wk post-TKA (physical activity and food recording); 2 wks post-TKA (blood draw, physical activity and food recording); 6 wks post-TKA (blood draw, MRI test, strength and functional mobility testing, physical activity and food recording, muscle and fat biopsy); 3 mos post-TKA (surveys, strength and functional mobility testing, physical activity and food recording); 6 mos post-TKA (surveys, DEXA scan, MRI test, strength and functional mobility testing, physical activity and food recording, muscle and fat biopsy), and 1 yr (surveys, DEXA scan, MRI test, strength and functional mobility testing, physical activity and food recording, muscle and fat biopsy).

Data will be collected from a variety of sources, including surveys, electronic medical records, medical and functional tests, and staff reports. Data will be entered and double-verified in password-protected spreadsheets sand databases stored behind a firewall. Any electronic medical records data captured will use secure data transfer and HIPAA-compliant protocols approved by the University of Oregon IRB. Staff reports will be forwarded directly to project data managers. All personal data will be identified by numbers rather than names. Interim reports of project results will be made to the Data and Safety Monitoring Board.

Power analyses indicated that a sample size of 80 subjects would be sufficient to detect anticipated effects on primary outcomes: operative leg quadriceps volume (MRI), non-operative leg quadriceps volume (MRI), isometric strength, Get Up And Go test, stair climb up test, stair climb down test, and six-minute walk test. The mean effect size across these outcomes, based on baseline- to 6-week percent change in pilot data) was d = 1.01, reflecting large effects. For a sample size of 30/group, this study can detect ESs of d > .79 with 85% power, and the minimally detectable ES drops to 0.68 or 0.52 with pretest covariates of r = .50 or .75. Every effort will be made to reduce attrition and obtain data on all participants at all assessment points. However, attrition is expected. Because this study will have power to detect anticipated physiological and functional effects with 30 subjects per condition, we will enroll 80 total subjects (40/condition) to account for possible attrition.