Mechanistic Approach to Preventing Atrophy and Restoring Function in Older Adults
Mechanistic Approach to Preventing Atrophy and Restoring Function in Older Adults
As a function of the growing population of older adults, an estimated 3.48 million total knee
 arthroplasty (TKA) procedures will be performed annually in the U.S. by 2030. Despite the
 near-universal success of this surgery in mitigating chronic knee pain, TKA is not successful
 in restoring long-term physical function in older adults, primarily because of quadriceps
 muscle atrophy, which explains 77% of the strength deficits. Overall, strength and functional
 mobility in TKA patients is 30-50% below age-matched healthy controls. Functional tasks such
 as stair-climbing remain a clinical problem for 75% of patients following TKA. Muscle atrophy
 occurs in both operative and non-operative legs, and is essentially permanent for older
 patients because of their impaired ability to increase muscle mass. The purpose of this
 clinical research is to determine the effects of essential amino acid (EAA) supplementation
 on muscle mass, strength, and functional mobility following TKA in older adults. Based on
 strong preliminary data, the investigators hypothesize that twice-daily ingestion of 23 g of
 EAA for 1 wk before through 6 wk after TKA will increase basal rates of muscle protein
 synthesis via inactivation of catabolic signaling, and up-regulation of anabolic and
 cyto-protective proteins. The investigators further hypothesize that short-term atrophy
 prevention and accelerated return of functional mobility will lead to longer-term structural
 and functional adaptations, and improved quality of life in older TKA patients vs. Placebo.
 Identifying the mechanisms up-regulated by EAA treatment that preserve muscle volume and
 mobility will have a major impact on rehabilitation science. This study will accomplish two
 specific aims: (1) determine if EAA elevates basal rates of muscle protein synthesis by
 up-regulating anabolic pathways and cyto-protective proteins, and inactivating catabolic
 pathways in the short term vs. Placebo and (2) determine if short-term prevention of atrophy,
 weakness, and functional mobility leads to positive changes in muscle cell structure and
 function, and improved quality of life in the longer term vs. Placebo. This work is
 significant because it advances knowledge of the molecular and cellular changes occurring
 during muscle atrophy (Placebo) and atrophy prevention (EAA) in a clinical setting using a
 treatment that is broadly applicable, is well tolerated, and can be implemented immediately.
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.

 The EAA intervention is designed to attenuate muscle loss, improve functional outcomes, and
 enhance quality of life. Data analyses will focus on shorter-term, longer-term results, and
 change over time. Preliminary analyses will employ descriptive statistics to understand the
 nature of the data and ensure that data distributions are appropriate for the statistical
 tests employed. Chi-square tests and analyses of variance, as appropriate, will be conducted
 to evaluate the equivalence of continuing participants vs. dropouts on demographic, medical
 history, and recent levels of dependent variables.

 We will conduct random coefficients analysis (RCA) to model muscle and functional mobility
 across time, as well as covariates that could affect outcomes, such as age, sex, physical
 activity, and dietary intake. RCA models trajectories from assessments nested within
 subjects; test of condition are represented by the interaction between a time factor and
 treatment condition. The RCA avoids the many pitfalls associated with traditional repeated
 measures ANOVA: It adjusts for within-individual dependence or autocorrelation in the data,
 can model nonlinear growth, does not require fixed spacing among assessments, and
 accommodates missing values over time. By using any available data across time, the RCA will
 limit the effects of missing data, reducing bias and increasing power. Based on our
 preliminary data, we estimate that we will be able to collect >92% of all data points.

 Expected study outcomes are as follows:

 1. With successful completion of this research, we expect to demonstrate that EAA prevents
 muscle atrophy bilaterally, as our preliminary data suggest. To date, it is not known if
 EAA can prevent atrophy.

 2. We expect to show that atrophy prevention will lead to strength gains and accelerated
 return of functional mobility. We further expect to show that EAA may have positive
 effects on central activation deficits, as our preliminary data suggest that strength is
 increased by 6 wks with EAA. To date, it is not known if preserving muscle following TKA
 will increase strength and augment the return of functional mobility.

 3. We expect to document that EAA will increase muscle cell size (CSA) bilaterally, in the
 vastus lateralis of the operative and non-operative quadriceps. It is not known if
 atrophy prevention and early return of functional mobility will stimulate positive gains
 in muscle cell structure.

 4. We expect to demonstrate that EAA increases mitochondrial mass bilaterally and increases
 mitochondrial respiration at rest. By sampling from the non-operative (control leg) and
 operative leg, we expect to show that EAA normalizes mitochondrial function over time (6
 mo and/or 1 yr post-TKA). It is not known if early gains in functional mobility will
 positively impact muscle cell function.

 5. We expect to show that quality of life (as measured by instruments such as VR-12) will
 be significantly increased with EAA. It is not known to what extent the above positive
 gains will have on longer-term (6 mo and 1 yr) quality of life.

 We expect each of the above to stimulate and be transformative. EAA supplements are
 inexpensive ($800/patient or $16/day), are well tolerated, and can be implemented
 immediately.
Inclusion Criteria:

 -  Age: between 50-80 years.

 -  Primary TKA surgery.

 Exclusion Criteria:

 1. Previous TKA and/or total hip arthroplasty surgery (older subjects).

 2. Dementia or related mental issues that may potentially put the subject at risk as
 determined by the surgeon.

 3. Untreated endocrine disease (Hypo/Hyperthyroidism, Addison's or Cushing's syndrome,
 etc.).

 4. Significant heart, liver, kidney, blood, or respiratory disease.

 5. Peripheral vascular disease.

 6. Active cancer.

 7. Recent (within 6 months) treatment with anabolic steroids.

 8. Alcohol or drug abuse.

 9. Inability to have MRI