Transcriptional pathways associated with skeletal muscle disuse atrophy in human

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Physiol Genomics. 2007 Sep 5

Transcriptional pathways associated with skeletal muscle disuse

atrophy in humans.

Chen YW, CM, Scarborough MT, Shi R, Walter GA, Vandenborne K.

Center for Genetic Medicine Research, Children's National Medical

Center and Washington University, Washington, District of

Columbia, United States.

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.