Montano Monty, Flanagan John N, Jiang Lan, Sebastiani Paola, Rarick Matthew, LeBrasseur Nathan K, Morris Carl A, Jasuja Ravi, Bhasin Shalender
Section of Infectious Diseases, Center for HIV-1/AIDS Care and Research, School of Public Health, Boston University, Boston, Massachusetts 02118, USA.
J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
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.
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.
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.
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.
即使在高效抗逆转录病毒治疗时代，与HIV相关的消瘦和体重减轻在临床上仍然是重大问题。尽管雄激素治疗可增加肌肉量，但其中涉及的细胞内在机制仍知之甚少。
本研究采用无偏倚方法，通过对骨骼肌活检组织进行全基因组微阵列分析，确定与睾酮治疗相关的表达谱。
设计、地点和参与者：44名体重减轻的HIV阳性男性被随机分为两组，分别接受每周一次300mg庚酸睾酮或安慰剂肌肉注射，共16周。在基线和治疗第14天获取肌肉活检组织。选择一部分标本进行微阵列分析，通过实时PCR、蛋白质印迹分析和肌肉前体细胞的体外培养来确认选定基因的变化。
与安慰剂组相比，接受睾酮治疗的受试者体重显著增加（分别为+2.05kg和-1.07kg；P=0.003），通过双能X线吸收法测得的瘦体重也显著增加（分别为2.93kg和0.35kg；P=0.003）。微阵列分析显示，参与肌发生、肌肉蛋白合成、免疫调节、代谢途径和染色质重塑的基因上调。通过实时PCR和蛋白质表达研究证实了代表性基因。在一项独立分析中，区分健康年轻男性与患有肌肉减少症的老年男性的基因网络与睾酮治疗激活的基因网络有大量重叠。
这些数据为雄激素作用机制提供了新见解，对肌肉生物标志物的开发以及消瘦和肌肉减少症的合成代谢疗法均有启示。
