Clinical trial NCT00760383: Muscle Regrowth During Physical Rehabilitation and Amino Acid Supplementation
Official title: Muscle Regrowth During Physical Rehabilitation and Amino Acid Supplementation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Osteoarthritis
Keywords: Total Knee Arthroplasty
Osteoarthritis
Muscle Metabolism
Rehabilitation
Physical Therapy
Lead sponsor: University of Oregon
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2008-09-26
Enrollment: 60
Sex: ALL
Minimum age (years): 60
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The general hypothesis is that in older adults muscle regrowth after an acute musculoskeletal stress will be positively influenced by traditional physical rehabilitation, and further enhanced by nutritional supplementation. Using state-of-the-art stable isotope methodologies for the study of muscle metabolism and methodologies for the measurement of cell signaling, we will test the following specific hypotheses: 1) Total knee arthroplasty (TKA) induces an acute net protein catabolism mainly by reducing muscle protein synthesis; 2) TKA induced catabolism is attenuated by the ingestion of essential amino acids (EAA); 3) EAA supplementation in combination with physical therapy (PT) will stimulate muscle protein synthesis and mTOR signaling to a greater extent than PT with Placebo; and 4) EAA supplementation during TKA PT rehabilitation will improve muscle strength, muscle volume and functional outcomes to a greater extent than PT with Placebo.

Public Benefit: This research will focus rehabilitation efforts on specific and currently unresolved mechanisms responsible for muscle loss following total knee replacement in older adults. While knee pain due to bone arthritis is often alleviated after knee replacement, complete return of physical function and independence is difficult to achieve. This research will help to restore physical function and independence in the rapidly growing population of older adults with knee arthritis.

Detailed description: The goal of this translational research project is to identify key mechanisms involved in regulating skeletal muscle loss and regrowth following total knee arthroplasty (TKA). Total knee arthroplasty induces significant declines in muscle mass and strength, which is directly responsible for reduced function, specifically functional independence. Such declines in muscle strength and volume and activities of daily living (getting up from a chair, climbing stairs and walking) can persist for up to 2 years.

Atrophy is the direct result of an imbalance between muscle protein synthesis and breakdown. However, there are two quite distinct mechanisms leading to muscle loss: accelerated protein breakdown (e.g. burn injury), primarily resulting from the stress response, or decreased protein synthesis (e.g., immobilization). In case of severe stress, muscle protein synthesis actually increases, although not adequately to impede muscle loss, and anabolic stimuli, such as nutrition, cannot counteract muscle atrophy. On the other hand, decreased protein synthesis from inactivity can be stimulated by nutrition and exercise, thereby reducing or preventing atrophy. Currently, we do not know which condition predominates following TKA: surgical stress-induced catabolism or immobility-associated declines in synthesis . What is not known is which signaling pathway predominates following TKA; stress induced catabolism or immobility associated declines in synthesis. Our goal is to determine which model (stress or inactivity) accounts for the acute and rapid muscle loss following TKA in order to better focus rehabilitation efforts.

Our general hypothesis is that quadriceps atrophy following TKA surgery is primarily due to inactivity, which can be counteracted by physical therapy (PT) and essential amino acid (EAA) supplementation. Our goal is to delineate the basic mechanisms underlying muscle loss with TKA, and based on this new information, to find novel rehabilitation strategies to accelerate recovery of normal function from TKA.

Thus, our plan is to test in older adults the following specific hypothesis:

1. TKA induces an acute and severe net protein catabolism by reducing muscle protein synthesis
2. TKA induced catabolism is attenuated with the ingestion of EAA
3. EAA supplementation following PT will stimulate muscle protein synthesis and mTOR signaling to a greater extent than PT with Placebo
4. EAA supplementation during TKA PT rehabilitation will improve muscle strength, muscle volume and functional outcomes to a greater extent than PT with Placebo

To test our specific hypothesis we will address the following specific aims:

1. To determine if TKA surgery reduces muscle protein synthesis and/or increases muscle protein breakdown
2. To determine if muscle protein synthesis is acutely increased with the ingestion of EAA following TKA surgery
3. To determine if muscle protein synthesis and mTOR signaling will be stimulated by PT rehabilitation and enhanced by EAA supplementation
4. To determine if EAA supplementation during TKA with traditional PT for 6 weeks improves muscle strength, muscle volume and functional outcomes This application will provide preliminary data for the submission of an R01 grant to further determine the mechanisms leading to successful return of quadriceps muscle strength and function following TKA. Essential amino acids are inexpensive, well tolerated and easily digestible and have been shown to independently stimulate muscle protein synthesis and components of the anabolic mTOR signaling pathway. My goal of increasing muscle strength and functional mobility is specifically outlined in the National Center for Medical Rehabilitation Research Seven Priority Areas and are in line with the NIH roadmap and priorities, and will help us to understand muscle protein metabolism during physical therapy rehabilitation. By adopting a mechanism-driven, translational research design that links changes in cell signaling with functional outcome measures (cell → system → function) we will capture key physiological events responsible for the regulation of muscle mass and function following TKA.

Eligibility criteria: Inclusion Criteria:

* Total Knee Arthroplasty surgical candidate

Exclusion Criteria:

* Overt muscle disease

Primary outcomes:
measure: Stair Time up
timeFrame: 6 weeks
measure: Quadriceps Muscle Strength
timeFrame: 6 weeks
Secondary outcomes:
measure: Mid-thigh Muscle Volume
timeFrame: 6 weeks
Other outcomes:
Locations:
city: Eugene
country: United States
facility: University of Oregon
state: Oregon
city: Eugene
country: United States
facility: Slocum Center for Orthopedics and Sports Medicine
state: Oregon
Study officials:
affiliation: Assistant Professor, Department of Human Physiology
name: Hans C Dreyer, PT, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dreyer HC, Drummond MJ, Pennings B, Fujita S, Glynn EL, Chinkes DL, Dhanani S, Volpi E, Rasmussen BB. Leucine-enriched essential amino acid and carbohydrate ingestion following resistance exercise enhances mTOR signaling and protein synthesis in human muscle. Am J Physiol Endocrinol Metab. 2008 Feb;294(2):E392-400. doi: 10.1152/ajpendo.00582.2007. Epub 2007 Dec 4.
citation: Fujita S, Dreyer HC, Drummond MJ, Glynn EL, Cadenas JG, Yoshizawa F, Volpi E, Rasmussen BB. Nutrient signalling in the regulation of human muscle protein synthesis. J Physiol. 2007 Jul 15;582(Pt 2):813-23. doi: 10.1113/jphysiol.2007.134593. Epub 2007 May 3.
citation: Dreyer HC, Fujita S, Cadenas JG, Chinkes DL, Volpi E, Rasmussen BB. Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle. J Physiol. 2006 Oct 15;576(Pt 2):613-24. doi: 10.1113/jphysiol.2006.113175. Epub 2006 Jul 27.
citation: Fujita S, Dreyer HC, Drummond MJ, Glynn EL, Volpi E, Rasmussen BB. Essential amino acid and carbohydrate ingestion before resistance exercise does not enhance postexercise muscle protein synthesis. J Appl Physiol (1985). 2009 May;106(5):1730-9. doi: 10.1152/japplphysiol.90395.2008. Epub 2008 Jun 5.
citation: Drummond MJ, Dreyer HC, Pennings B, Fry CS, Dhanani S, Dillon EL, Sheffield-Moore M, Volpi E, Rasmussen BB. Skeletal muscle protein anabolic response to resistance exercise and essential amino acids is delayed with aging. J Appl Physiol (1985). 2008 May;104(5):1452-61. doi: 10.1152/japplphysiol.00021.2008. Epub 2008 Mar 6.
citation: Dreyer HC, Blanco CE, Sattler FR, Schroeder ET, Wiswell RA. Satellite cell numbers in young and older men 24 hours after eccentric exercise. Muscle Nerve. 2006 Feb;33(2):242-53. doi: 10.1002/mus.20461.
citation: Dreyer HC, Volpi E. Role of protein and amino acids in the pathophysiology and treatment of sarcopenia. J Am Coll Nutr. 2005 Apr;24(2):140S-145S. doi: 10.1080/07315724.2005.10719455.
citation: Ratchford SM, Bailey AN, Senesac HA, Hocker AD, Smolkowski K, Lantz BA, Jewett BA, Gilbert JS, Dreyer HC. Proteins regulating cap-dependent translation are downregulated during total knee arthroplasty. Am J Physiol Regul Integr Comp Physiol. 2012 Mar 15;302(6):R702-11. doi: 10.1152/ajpregu.00601.2011. Epub 2011 Dec 28.
citation: Dreyer HC, Strycker LA, Senesac HA, Hocker AD, Smolkowski K, Shah SN, Jewett BA. Essential amino acid supplementation in patients following total knee arthroplasty. J Clin Invest. 2013 Nov;123(11):4654-66. doi: 10.1172/JCI70160. Epub 2013 Oct 25.