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1 Center for Genetic Medicine Research, Children's National Medical Center and George Washington University, Washington, District of Columbia, United States
2 Department of Physical Therapy, University of Florida, Gainesville, Florida, United States; Brain Rehabilitation Research Center, Malcom Randall VA Medical center, Gainesville, Georgia, United States
3 University of Florida, Department of Orthopaedics, Gainesville, Florida, United States
4 Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida, United States
5 Department of Physical Therapy, University of Florida, Gainesville, Florida, United States
* To whom correspondence should be addressed. E-mail: kvandenb{at}phhp.ufl.edu.
Disuse atrophy is a common clinical phenomenon which significantly impacts muscle function and activities of daily living. The purpose of this study was to implement genome wide expression profiling to identify transcriptional pathways associated with muscle remodeling in a clinical model of disuse. Skeletal muscle biopsies were acquired from the medial gastrocnemius in patients with an ankle fracture and from healthy volunteers subjected to 4-11 days of cast-immobilization. We identified 277 misregulated transcripts in immobilized muscles of patients, of which the majority were downregulated. The most broadly affected pathways were involved in energy metabolism, mitochondrial function, and cell cycle regulation. We also found decreased expression in genes encoding proteolytic proteins, calpain 3 and calpastatin, and members of the myostatin and IGF-I pathway. Only 26 genes showed increased expression in immobilized muscles, including apolipoprotein (APOD) and leptin-receptor (LEPR). Upregulation of APOD (5.0 fold, p<0.001) and LEPR (5.7 fold, p<0.05) was confirmed by quantitative RT-PCR and immunohistochemistry. In addition, atrogin-1/MAFbx was found 2.4 fold upregulated (p<0.005) by quantitative RT-PCR. Interestingly, 96% of the transcripts differentially regulated in immobilized limbs also showed the same trend of change in the contralateral legs of patients, but not the contralateral legs of healthy volunteers. Information obtained in this study complements findings in animal models of disuse and provides important feedback for future clinical studies targeting the restoration of muscle function following limb disuse in humans.
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