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Skeletal muscle displays an extensive capacity to adapt to a wide range of metabolic and mechanical stressors. As an insulin-sensitive and exercise-responding tissue, it plays a key role in the context of therapeutic interventions targeting metabolic diseases including type 2 diabetes (T2D) and obesity. The aim of this thesis was to gain mechanistic insight into the adaptive response of skeletal muscle to different genetic and environmental stressors by using in vitro and in vivo models. This work, with a unique in vitro longitudinal model, has allowed the broadening of knowledge about how skeletal muscle adapts to weight-loss surgery. Notably, glucose storage as glycogen, but not fatty acid oxidation was improved in myotubes derived from skeletal muscle biopsies from patients who underwent gastric bypass surgery. Potential new targets mediating the metabolic effects of surgery in skeletal muscle include proline-rich Akt substrate of 40kDa (PRAS40). By genotyping a cohort of individuals with either normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or T2D, the impact of the ACTN3 R577X polymorphism on metabolic disease was evaluated. A higher proportion of T2D patients with the homozygous null allele (577XX) was detected, but no further association with clinical parameters could be established. Rather, the presence of the 577XX genotype is associated with increased mRNA levels of genes involved in structural integrity of skeletal muscle. Surgical removal of synergistic skeletal muscle to induce functional overload and hypertrophy in the plantaris muscle of genetically modified mice addressed whether the γ3 subunit of the energy cell sensor AMPK plays a role in skeletal muscle remodeling in the context of hypertrophy. Following a 14-day functional overload, skeletal muscle of transgenic (R225Q), knockout and wild-type mouse models underwent a similar hypertrophic response, as demonstrated by functional, transcriptional and signaling data. Due to increased mass at baseline, the plantaris muscle of R225Q mice underwent a smaller change in weight gain. Overall, this work demonstrates that the AMPK γ3 isoform is dispensable for skeletal muscle hypertrophy. Collectively, the results presented in this thesis provide new information about the remodeling capacity of skeletal muscle in response to the above-mentioned stressors. Environmental and genetic factors affect skeletal muscle by modifying local signaling pathways and inducing changes in energy metabolism, subsequently impacting whole-body energy homeostasis.