Androgen receptor regulates expression of skeletal muscle-specific proteins and muscle cell types
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gen Receptor Regulates Expression of Skeletal Muscle–Specific Proteins and Muscle Cell Types Saleh Altuwaijri,1 Dong Kun Lee,1 Kuang-Hsiang Chuang,1 Huei-Ju Ting,1 Zhiming Yang,1 Qingquan Xu,1 Meng-Yin Tsai,2 Shuyuan Yeh,1 LeRoy A. Hanchett,1 Hong-Chiang Chang,3 and Chawnshang Chang1 1
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and The Cancer Center, University of Rochester Medical Center, Rochester, New York 14642; 2Department of OB/GYN, Chang Gang University. Kaohsiung 833, Taiwan; and 3Department of Urology, National Taiwan University, Taipei 100, Taiwan
C2C12 myoblasts expressing the androgen receptor (AR) were used to analyze the role of androgen–AR signaling pathway in skeletal muscle development. Marked up-regulation of AR expression was observed in differentiated myotubes. A nuclear run-on transcription assay demonstrated that transcription of the AR gene is increased during skeletal muscle cell differentiation. Regulation of skeletal muscle–specific protein expression by the androgen–AR signaling pathway was further analyzed using quadriceps skeletal muscle from wild-type (WT) and AR knock-out (ARKO) male mice. A histological analysis of quadriceps skeletal muscle indicates no morphological differences between ARKO and WT mice. However, the androgen–AR signaling pathway increases expression of slow-twitch–specific skeletal muscle proteins and downregulates fast-twitch–specific skeletal muscle proteins, resulting in an increase of slow-twitch muscle fiber type cells in quadriceps muscle.
The androgen–AR signaling pathway has been reported to play key roles in determination of sexual differentiation as well as development of sex accessory organs (reviewed in refs. 1 and 2). In addition, AR has been reported to be expressed in non-reproductive tissues, such as brain, kidney, liver, and muscle. Animal studies using frogs indicate that androgen is required for appropriate development of sexually dimorphic skeletal muscles (reviewed in ref. 2). Animal studies showed that administration of testosterone (T) resulted in skeletal muscle hypertrophy and increase of AR expression (9,10). Consistent with the animal studies, clinical studies showed that T might induce skeletal muscle cell hypertrophy by enhancing AR expression followed by increasing muscle protein synthesis (reviewed in refs. 11 and 12). Individual skeletal muscle fiber cells are distinguished by the presence of multiple elongated nuclei located just beneath the cell membrane (sarcolemma), and the presence of regular cross-striations resulting from the particular arrangement of the contractile proteins, such as actin and myosin (reviewed in ref. 13). Individual muscle fibers are polygonal in shape, and bundles of muscle fibers are surrounded by a dense layer of collagen. On the basis of the adenosine triphosphatase histochemical reactions, muscle cell types of adult muscle are divided into type I, type IIA, and type IIB (reviewed in ref. 14). In general, individual skeletal muscles contain both slow-twitch and fast-twitc
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