TRT during LT selectively enhances skeletal muscle glycolysis, identifying glycolytic activation as the dominant metabolic adaptation in older men with obesity and hypogonadism.
Key Findings
Results
Among the metabolic pathways examined, only glycolysis showed a consistent and significant response to LT+TRT versus LT+Pbo.
Between-group p = 0.005 for glycolysis pathway response
The pentose phosphate pathway showed limited changes
Neither the TCA cycle nor carnitine metabolites exhibited consistent patterns
Analysis was based on targeted LC-MS/MS of vastus lateralis biopsies in 44 participants from the 83-person LITROS trial
Results
The glycolytic response to LT+TRT was characterized by increases in both preparatory and payoff phase intermediates along with higher lactate concentrations.
Preparatory phase intermediates increased: G6P/F6P and FBP
Payoff phase intermediates increased: 3PG, 2PG, and PEP
Lactate concentrations were higher in LT+TRT
Pyruvate remained stable despite increased glycolytic flux
Results
The glycolysis factor score in LT+TRT was positively correlated with VO2peak and inversely correlated with triglycerides and metabolic syndrome score.
Glycolysis factor score correlated positively with VO2peak (r=0.47, p=0.04)
Glycolysis factor score correlated inversely with triglycerides (r=-0.52, p=0.01)
No significant correlations were observed in the LT+Pbo group
Methods
The study was a randomized, double-blind, placebo-controlled trial (LITROS) enrolling 83 older men with obesity, hypogonadism, and frailty for 26 weeks.
Participants were aged 65 years or older with BMI ≥30 kg/m2
Hypogonadism defined as testosterone <10.4 nmol/L
Frailty defined as Physical Performance Test score ≤31
Participants were randomized to LT plus TRT or LT plus placebo for 26 weeks
A metabolomic substudy was performed in 44 of the 83 participants using serial vastus lateralis biopsies
Discussion
The authors propose that TRT-enhanced glycolytic flux under caloric restriction may support muscle and bone preservation by efficiently generating ATP while conserving amino acids.
Increased glycolytic flux is hypothesized to produce efficient ATP generation under calorie restriction
Amino acid conservation is proposed as a mechanism supporting muscle and bone preservation
The metabolic adaptation is also proposed to improve aerobic and cardiometabolic function
Weight loss in older men with obesity and hypogonadism was noted to accelerate musculoskeletal decline without TRT
Viola V, Aguilar M, Nava M, Celli A, Armamento-Villareal R, Barnouin Y, et al.. (2026). Testosterone plus lifestyle therapy improves skeletal muscle glycolysis in older men with obesity and hypogonadism.. Frontiers in endocrinology. https://doi.org/10.3389/fendo.2025.1719749