biostudies-literatureUnknown16Viola V<h4>Objective</h4>Weight loss in older men with obesity and hypogonadism accelerates musculoskeletal decline, yet the underlying metabolic mechanisms remain unclear. Testosterone replacement therapy (TRT), when added to lifestyle therapy (LT), mitigates this decline, but its metabolic basis has not been defined. We examined skeletal muscle metabolomic adaptations to LT with or without TRT, focusing on glycolysis, the pentose phosphate pathway (PPP), the tricarboxylic acid (TCA) cycle, and carnitine metabolism to identify dominant pathways of metabolic adaptation.<h4>Design</h4>Randomized, double-blind, placebo-controlled trial (LITROS).<h4>Methods</h4>Eighty-three men aged 65 years or older with obesity (BMI ≥30 kg/m²), hypogonadism (testosterone <10.4 nmol/L), and frailty (PhysFrontiers in endocrinology1719749https://www.ebi.ac.uk/biostudies/studies/S-EPMC12914099biostudies-literatureTestosterone plus lifestyle therapy improves skeletal muscle glycolysis in older men with obesity and hypogonadism.PMC12914099Armamento-Villareal RBarnouin YViola VCelli ANapoli NNava MLDQualls CVillareal DTPutluri NAguilar MfalseTestosterone plus lifestyle therapy improves skeletal muscle glycolysis in older men with obesity and hypogonadism.<h4>Objective</h4>Weight loss in older men with obesity and hypogonadism accelerates musculoskeletal decline, yet the underlying metabolic mechanisms remain unclear. Testosterone replacement therapy (TRT), when added to lifestyle therapy (LT), mitigates this decline, but its metabolic basis has not been defined. We examined skeletal muscle metabolomic adaptations to LT with or without TRT, focusing on glycolysis, the pentose phosphate pathway (PPP), the tricarboxylic acid (TCA) cycle, and carnitine metabolism to identify dominant pathways of metabolic adaptation.<h4>Design</h4>Randomized, double-blind, placebo-controlled trial (LITROS).<h4>Methods</h4>Eighty-three men aged 65 years or older with obesity (BMI ≥30 kg/m²), hypogonadism (testosterone <10.4 nmol/L), and frailty (Phys2025-01-01T00:00:00Z20252026-07-16T18:47:01.454Z2026-07-12T03:07:47.861ZS-EPMC129140994171648710.3389/fendo.2025.1719749