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.
Key Findings
Results
Lean body mass and thigh muscle volume decreased less in LT+TRT than LT+Pbo despite similar weight loss.
Both groups achieved approximately 10% weight loss.
Lean body mass and thigh muscle volume decreased -2% in LT+TRT vs. -4% in LT+Pbo (p = 0.04).
Study population: 38 older men (≥65 years) with obesity (BMI ≥30 kg/m²) and hypogonadism (testosterone persistently <300 ng/dL) who underwent serial muscle biopsies from a 26-week trial.
Participants also had frailty defined by Modified Physical Performance Test score ≤31.
Results
Hip bone mineral density (BMD) was preserved in LT+TRT compared with LT+Pbo.
Hip BMD changed +0.4% in LT+TRT vs. -1.3% in LT+Pbo (p = 0.03).
This finding was from the 26-week LITROS trial substudy.
A bone-related pathway (bone mineralization involved in bone maturation) was downregulated only in LT+Pbo, not in LT+TRT.
Results
Muscle strength increased similarly in both treatment groups.
Muscle strength increased 23% in LT+TRT vs. 24% in LT+Pbo (p = 0.95).
This indicates that the addition of TRT did not confer additional benefit on muscle strength beyond lifestyle therapy alone.
Results
Total testosterone increased significantly more in LT+TRT than LT+Pbo.
Total testosterone increased 133% in LT+TRT vs. 32% in LT+Pbo (p = 0.005).
The intervention duration was 26 weeks.
Results
Next Generation Sequencing identified distinct sets of differentially expressed genes in each treatment group.
Of the 39,160 genes detected in LT+TRT and 39,115 genes detected in LT+Pbo, 195 were differentially expressed in LT+TRT and 158 in LT+Pbo.
Serial muscle biopsies were performed in 38 participants from the LITROS trial.
Gene expression profiling was performed using Next Generation Sequencing.
Results
Gene Ontology enrichment analyses revealed fewer downregulated muscle-related pathways in LT+TRT compared with LT+Pbo.
In LT+TRT, four muscle-related pathways were downregulated: muscle organ development, muscle organ morphogenesis, regulation of skeletal muscle contraction, and muscle atrophy.
In LT+Pbo, nine muscle-related pathways were downregulated: 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, and muscle atrophy.
The pathway 'muscle system process' was upregulated in LT+TRT but downregulated in LT+Pbo.
One bone-related pathway (bone mineralization involved in bone maturation) was downregulated only in LT+Pbo.
Results
LT+TRT resulted in higher expression of MYOD1 and WNT4 compared with LT+Pbo.
MYOD1 expression was significantly higher in LT+TRT vs. LT+Pbo (p = 0.02); MYOD1 is a key gene involved in muscle metabolism.
WNT4 expression was significantly higher in LT+TRT vs. LT+Pbo (p = 0.02); WNT4 is a key gene involved in bone metabolism.
These findings were confirmed by RT-PCR analyses.
Results
LT+TRT resulted in significantly higher mRNA expression of MYBPH, SCN3B, and DSC2, genes involved in the muscle system process.
MYBPH expression was significantly higher in LT+TRT vs. LT+Pbo (p = 0.006).
SCN3B expression was significantly higher in LT+TRT vs. LT+Pbo (p = 0.02).
DSC2 expression was significantly higher in LT+TRT vs. LT+Pbo (p = 0.01).
These genes are involved in the muscle system process pathway.
Viola V, Samanta T, Nava M, Celli A, Armamento-Villareal R, Nguyen N, et al.. (2025). Testosterone Modulation of Muscle Transcriptomic Profile During Lifestyle Therapy in Older Men with Obesity and Hypogonadism.. Journal of cachexia, sarcopenia and muscle. https://doi.org/10.1002/jcsm.13697