Mitochondrial diseases (MD) comprise a range of debilitating and life threatening conditions, which can arise from genetic defects in either the mitochondrial or nuclear genomes. One of the most common genes implicated in human mitochondrialopathies is DNA Polymerase γ (PolG1), which has primary roles in replicating and repairing mtDNA. Studies in both humans and rodents have demonstrated that deleterious mutations in the PolG1 gene result in a wide range of pathologies across various tissues that contribute to the progression of MD. However, the intrinsic, tissue specific impacts of PolG defects have been mostly unresolved, largely because inherited, germline mutations in PolG precipitate complex, multi-organ pathologies. Thus, towards investigating the tissue specific effects of PolG pathologies, we hereto within describe what is to our knowledge, the first conditional PolG mutator mouse (PolGfl/fl Mutator). This was generated by flanking exons 4-5 of the PolG gene with LoxP sites, which upon recombination induces an in-frame truncation that lacks exonuclease activity. We validate and characterise this model using an inducible, skeletal muscle specific cre-model (ACTA1-cre-ERT2), which we followed for up to 12 months. We demonstrate minimal gross phenotypic impacts in these animals until ~5-months post-mutation, after which mice rapidly develop cardinal features of mitochondrial dysfunction described in other models of skeletal muscle mitochondrial dysfunction. This included sudden and significant weight loss, which upon in-depth multi-omics profiling was demonstrated to be driven by a profound loss of mitochondrial protein translation and Complex I activity, leading to activation of the integrated stress response and marked expression of FGF21 and GDF15. Thus, these data provide the first insights into the systemic impacts of a tissue specific mutator model, paving the way for future work in this area, and providing a greater understanding of the pathways and pathologies that underlie PolG induced MD in humans.