Viola Viola, Samanta Tagari, Nava Maria Liza Duremdes, Celli Alessandra, Armamento-Villareal Reina, Nguyen Ngoc Ho Lam, Colleluori Georgia, Barnouin Yoann, Napoli Nicola, Qualls Clifford, Kaipparettu Benny Abraham, Villareal Dennis T
Center for Translational Research on Inflammatory Diseases, Michael E DeBakey VA Medical Center, Houston, Texas, USA.
Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, Texas, USA.
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1):e13697. doi: 10.1002/jcsm.13697.
Testosterone replacement therapy (TRT) added to lifestyle therapy can mitigate weight-loss-induced reduction of muscle mass and bone mineral density (BMD) in older men with obesity and hypogonadism.
To investigate the molecular mechanisms underlying the attenuation of muscle and BMD loss in response to TRT during intensive lifestyle intervention in this high-risk older population.
Among 83 older (≥ 65 years) men with obesity (BMI ≥ 30 kg/m) and hypogonadism (early AM testosterone persistently < 300 ng/dL) associated with frailty (Modified Physical Performance Test score ≤ 31) randomized into 26-week lifestyle therapy plus testosterone (LT+TRT) or placebo (LT+Pbo) in the LITROS trial, 38 underwent serial muscle biopsies for the muscle transcriptomics substudy.
Despite similar ~10% weight loss, lean body mass and thigh muscle volume decreased less in LT+TRT than LT+Pbo (-2% vs. -4%, respectively; p = 0.04). Hip BMD was preserved in LT+TRT compared with LT+Pbo (0.4% vs. -1.3%; p = 0.03). Muscle strength increased similarly in LT+TRT and LT+Pbo (23% vs. 24%; p = 0.95). Total testosterone increased more in LT+TRT than LT+Pbo (133% vs. 32%; p = 0.005). Based on Next Generation Sequencing, of the 39 160 and 39 115 genes detected in LT+TRT and LT+Pbo, respectively, 195 were differentially expressed in LT+TRT and 158 in LT+Pbo. Gene Ontology enrichment analyses revealed that in LT+TRT, just four muscle-related pathways (muscle organ development, muscle organ morphogenesis, regulation of skeletal muscle contraction, muscle atrophy) were downregulated and one pathway (muscle system process) was upregulated. In contrast, in LT+Pbo, nine muscle-related pathways (muscle system process, muscle tissue development, muscle organ development, skeletal muscle tissue development, skeletal muscle organ development, skeletal muscle cell differentiation, muscle organ morphogenesis, response to stimuli involved in regulation of muscle adaptation, muscle atrophy) and one pathway related to bone (bone mineralization involved in bone maturation) were downregulated. Muscle system process was upregulated in LT+TRT but downregulated in LT+Pbo. RT-PCR analyses showed that LT+TRT resulted in a higher expression of MYOD1 (p = 0.02) and WNT4 (p = 0.02), key genes involved in muscle and bone metabolism, respectively, compared with LT+Pbo. We also observed significantly higher mRNA expression of MYBPH (p = 0.006), SCN3B (p = 0.02) and DSC2 (p = 0.01), genes involved in the muscle system process, in response to LT+TRT compared with LT+Pbo.
The addition of TRT to lifestyle therapy mitigates the weight-loss-induced reduction of muscle mass and BMD via countering the weight-loss-induced downregulation of genes involved in muscle and bone anabolism.
对于患有肥胖症和性腺功能减退的老年男性，在生活方式治疗基础上添加睾酮替代疗法（TRT）可减轻体重减轻引起的肌肉量和骨矿物质密度（BMD）降低。
探讨在这一高危老年人群的强化生活方式干预期间，TRT减轻肌肉和BMD损失的分子机制。
在LITROS试验中，83名年龄≥65岁、患有肥胖症（BMI≥30kg/m²）和性腺功能减退（清晨睾酮持续<300ng/dL）且伴有虚弱（改良体能测试评分≤31）的男性被随机分为接受26周生活方式治疗加睾酮（LT+TRT）或安慰剂（LT+Pbo），其中38人接受了系列肌肉活检以进行肌肉转录组学子研究。
尽管体重减轻幅度相似，均约为10%，但LT+TRT组的去脂体重和大腿肌肉体积减少幅度小于LT+Pbo组（分别为-2%和-4%；p=0.04）。与LT+Pbo组相比，LT+TRT组的髋部BMD得以保留（0.4%对-1.3%；p=0.03）。LT+TRT组和LT+Pbo组的肌肉力量增加幅度相似（分别为23%和24%；p=0.95）。LT+TRT组的总睾酮增加幅度大于LT+Pbo组（133%对32%；p=0.005）。基于二代测序，LT+TRT组和LT+Pbo组分别检测到39160个和39115个基因，其中195个基因在LT+TRT组中差异表达，158个基因在LT+Pbo组中差异表达。基因本体富集分析显示，在LT+TRT组中，仅有四个与肌肉相关的通路（肌肉器官发育、肌肉器官形态发生、骨骼肌收缩调节、肌肉萎缩）下调，一个通路（肌肉系统过程）上调。相比之下，在LT+Pbo组中，九个与肌肉相关的通路（肌肉系统过程、肌肉组织发育、肌肉器官发育、骨骼肌组织发育、骨骼肌器官发育、骨骼肌细胞分化、肌肉器官形态发生、参与肌肉适应调节的刺激反应、肌肉萎缩）和一个与骨骼相关的通路（参与骨骼成熟的骨矿化）下调。肌肉系统过程在LT+TRT组中上调，但在LT+Pbo组中下调。逆转录聚合酶链反应分析显示，与LT+Pbo组相比，LT+TRT组中分别参与肌肉和骨骼代谢的关键基因MYOD1（p=0.02）和WNT4（p=0.02）的表达更高。与LT+Pbo组相比，我们还观察到在LT+TRT组中，参与肌肉系统过程的基因MYBPH（p=0.006）、SCN3B（p=0.02）和DSC2（p=0.01）的mRNA表达显著更高。
在生活方式治疗基础上添加TRT可通过对抗体重减轻引起的参与肌肉和骨骼合成代谢的基因下调，减轻体重减轻引起的肌肉量和BMD降低。
