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Transcriptional Profiling of Testosterone-Regulated Genes in the Skeletal Muscle of Human Immunodeficiency Virus-Infected Men Experiencing Weight Loss

Sections of Infectious Diseases (M.M., M.R.) and Endocrinology, Diabetes, and Nutrition (J.N.F., L.J., N.K.L., C.A.M., R.J., S.B.), Center for HIV-1/AIDS Care and Research (M.M., M.R.), School of Medicine, and Department of Biostatistics (P.S.), School of Public Health, Boston University, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Monty Montano, Ph.D., 650 Albany Street, EBRC 640, Boston University School of Medicine, Boston, Massachusetts 02118. E-mail: mmontano{at}bu.edu.

Context: HIV-associated wasting and weight loss remain clinically significant concerns even in the era of potent antiretroviral therapy. Although androgen treatment increases muscle mass, the cell-intrinsic mechanisms engaged remain poorly understood.

Objective: This study was an unbiased approach to identify expression profiles associated with testosterone treatment using genome-wide microarray analysis of skeletal muscle biopsies.

Design, Setting, and Participants: Forty-four HIV-positive men with weight loss were randomized to receive either 300 mg testosterone enanthate or placebo injections im weekly for 16 wk. Muscle biopsies were obtained at baseline and on treatment d 14. A subset of specimens was chosen for microarray analysis, with changes in selected genes confirmed by real-time PCR, Western blot analysis, and in vitro culture of muscle precursor cells.

Results: Significantly greater gains in body mass (+2.05 and –1.07 kg, respectively; P = 0.003) and lean body mass by dual-energy x-ray absorptiometry (2.93 vs. 0.35 kg, respectively; P = 0.003) were observed in subjects treated with testosterone compared with placebo. Microarray analysis revealed up-regulation in genes involved in myogenesis and muscle protein synthesis, immune regulation, metabolic pathways, and chromatin remodeling. Representative genes were confirmed by real-time PCR and protein expression studies. In an independent analysis, gene networks that differentiate healthy young men from older men with sarcopenia had substantial overlap with those activated by testosterone treatment.

Conclusions: These data provide new insights into the mechanisms of androgen action and have implications for both development of muscle biomarkers and anabolic therapies for wasting and sarcopenia.