A growing number of children and adolescents seeks gender-affirming care, comprising puberty-suppressing agents while awaiting future gender-affirming hormone treatment. The long-term impact of this approach on skeletal muscle, an important tissue for healthy aging, is unknown. Given the crucial role of sex hormones in muscular development, we postulate that these hormonal manipulations initiated at the earliest pubertal stages modify muscle cell properties, resulting in an altered adaptive response of skeletal muscle upon future stimuli that induce muscular atrophy or regeneration. We will test this hypothesis using translational mouse models mimicking the clinical strategy that is applied in transgender youth, and will take the first steps in translating these findings to humans. This project will unveil important and novel insight in the effects of gender-affirming therapy started in early puberty on skeletal muscle and the underlying cellular and molecular mechanisms, which may ultimately be leveraged for optimizing medical care for young-adolescent transgender individuals.