Patients with single, large-scale mitochondrial DNA (mtDNA) deletions often present with mitochondrial myopathy (MM) for which no treatment is available. Exercise intervention induces beneficial effects in mitochondrial myopathy. However, the mechanisms for this are not yet understood. The aim of this study is to investigate genetic, biochemical and molecular changes triggered by 16-week resistance exercise training for the development of exercise mimetic drugs for the cure of MM patients. Quadriceps biopsies were taken from a cohort of single, large-scale mtDNA deletion patients before and after 16-week resistance exercise training. Biopsies were assessed for changes after exercise in oxidative phosphorylation (OXPHOS) staining for Laminin, VDAC1, Ndufb8 and COX1; fibre type distribution, size and contraction force staining for Myh7, Myh2 and Myh1; heteroplasmy using real-time PCR for MT-ND4, MT-CO1, MT-CO3 and MT-CYB genes; differentially expressed (DE) genes and related protein level using RNA-sequencing and imaging mass cytometry, respectively. Myopathy score is a strong predictor of resistance exercise training responsiveness. Compared to healthy controls, all patients present with a significantly lower contraction force of SKM fibres (p=0.003) and differential fibre type distribution with increased type 2a (p<0.04) and decreased fibre I (p<0.0001). After exercise, all cases show an increase in the proportion of fibres with higher level of COX1 (p<0.0012) and increase of Myh7<sup>+</sup> fibre type size (all patients except P2, p < 0.0001). The majority of patients show a significant increase of mitochondrial mass that positively correlates with the increase of aerobic capability (R=0.81). Furthermore, 13,132 DE genes were identified between pre- and post-exercise cases, of which 40 DE genes were selected with p<0.05 and logarithmic fold change <1.5 or >1.5. Among these, 13 novel exercise-modulated targets were established with an increased protein level localising within the SKM fibres (e.g. Dock11, Edil3, Ikbkg, Gem). Further analysis will assess the protein level of targets with nuclear, perinuclear and extracellular localisation in SKM of MM patients. Resistance exercise training is effective in reducing the OXPHOS defects and induces SKM remodelling in MM patients. The identification of novel exercise-modulated targets may provide insight for the development of exercise mimetic drugs for the cure of mitochondrial myopathy patients.