Muscle atrophy and weakness secondary to disuse are common clinical phenomena, which can significantly impact activities of daily living and present a major challenge in rehabilitation. Rehabilitation programs designed to maximize strength gains may not be optimal, and the speed and extent of recovery is highly variable between individuals. We will identify the molecular (transcriptional) signatures associated with muscle remodeling in response to rehabilitation in a patient cohort. The key hypothesis of this proposal is that the rate and extent of functional recovery during rehabilitation following limb disuse correlates with the extent of induction of four remodeling signatures eccentric/damage, TGFbeta/MAPK, atrophy and aerobic conditioning) previously identified by this investigative team. 60 patients with a closed malleolus fracture, treated conservatively using a short leg cast for a period of 6 weeks will be recruited. Following cast-immobilization, subjects will be enrolled in a standardized 6-week rehabilitation program (3 sessions/week) focusing on progressive resistance training of the ankle plantar flexor muscles. The phenotypic response (Aim 1) to cast-immobilization and rehabilitation will be assessed in all individuals using isokinetic testing, magnetic resonance imaging and functional assessment tests. Phenotypic measurements will be performed before, during and immediately after the rehabilitation intervention. Ankle plantar flexor muscle size and strength measurements will also be performed on the uninvolved limb (serves as a control) at 6 months post-immobilization.
In Aim 2, four longitudinal biopsies will be taken from the medial gastrocnemius of each individual and expression profiled over the entire human genome (U133A/B). The first 30 individuals will be used as the data generation """"""""test set"""""""" (years 1-3), and the second 30 individuals as a """"""""validation set"""""""" (years 3-5).
In Aim 3, we will determine the correlation between the phenotypes defined in Aim 1 (percentage change in size, muscle strength, functional performance), and the """"""""relative induction/repression"""""""" of the four remodeling signatures (eccentric/damage, TGFbeta/MAPK, muscle atrophy and aerobic conditioning). The development of effective therapeutic interventions targeting restoration of muscle function necessitates an in-depth understanding of the cellular and molecular mechanisms mediating muscle atrophy and subsequent repair. We anticipate that this study will provide essential feedback for the design and development of effective, individualized, rehabilitation interventions.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD048051-01
Application #
6837058
Study Section
Special Emphasis Panel (ZHD1-DSR-R (25))
Program Officer
Nitkin, Ralph M
Project Start
2004-09-28
Project End
2009-07-31
Budget Start
2004-09-28
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$336,430
Indirect Cost
Name
University of Florida
Department
Other Health Professions
Type
Schools of Public Health
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Chen, Yi-Wen; Gregory, Chris; Ye, Fan et al. (2017) Molecular signatures of differential responses to exercise trainings during rehabilitation. Biomed Genet Genom 2:
Baligand, Celine; Chen, Yi-Wen; Ye, Fan et al. (2015) Transcriptional Pathways Associated with Skeletal Muscle Changes after Spinal Cord Injury and Treadmill Locomotor Training. Biomed Res Int 2015:387090
Kostek, Matthew C; Nagaraju, Kanneboyina; Pistilli, Emidio et al. (2012) IL-6 signaling blockade increases inflammation but does not affect muscle function in the mdx mouse. BMC Musculoskelet Disord 13:106
Kostek, Matthew C; Chen, Yi-Wen; Cuthbertson, Daniel J et al. (2007) Gene expression responses over 24 h to lengthening and shortening contractions in human muscle: major changes in CSRP3, MUSTN1, SIX1, and FBXO32. Physiol Genomics 31:42-52
Gregory, Chris M; Dixon, Warren; Bickel, C Scott (2007) Impact of varying pulse frequency and duration on muscle torque production and fatigue. Muscle Nerve 35:504-9
Chen, Yi-Wen; Gregory, Chris M; Scarborough, Mark T et al. (2007) Transcriptional pathways associated with skeletal muscle disuse atrophy in humans. Physiol Genomics 31:510-20
Stevens, Jennifer E; Pathare, Neeti C; Tillman, Susan M et al. (2006) Relative contributions of muscle activation and muscle size to plantarflexor torque during rehabilitation after immobilization. J Orthop Res 24:1729-36
Pathare, Neeti C; Stevens, Jennifer E; Walter, Glenn A et al. (2006) Deficit in human muscle strength with cast immobilization: contribution of inorganic phosphate. Eur J Appl Physiol 98:71-8