Fig. 1: Generation of a post-developmental muscle specific PolG exonuclease mutant mouse with detrimental effects on muscle function and whole-body parameters.

A Abundance of each exon across the Polg1 gene, as determined by RNAseq, in skeletal muscle in PolG^mut (red bars) compared to control (PolG^cont, black bars) mice, n = 6/group. B Mutation rate (fold change from control) in skeletal muscle mtDNA of PolG^mut and D257A Mutator mice in short or long-term cohorts compared to their respective controls, (short-term/long-term/mutator: PolG^cont n = 6/5/5 & PolG^mut n = 11/6/6). C Amplification rate (fold change from control) of a control mtDNA region of skeletal muscle mtDNA in PolG^mut and D257A Mutator in short or long-term cohorts compared to their respective controls, (short-term/long-term/mutator: PolG^cont n = 9/4/5 & PolG^mut n = 8/4/5). D Heatmap representing Log₂ fold change of mitochondrial RNA transcript abundance in PolG^mut compared with PolG^cont, as determined by RNA-sequencing in skeletal muscle. E Abundance of mtDNA encoded proteins in PolG^mut mice relative to PolG^cont mice presented as percent from control, as determined by proteomics, n = 5/group. Phenotyping data in short and long-term cohorts of PolG^cont and PolG^mut mice (F) Weekly body weights in the short-term and (G) long-term cohorts. H Lean mass in the short-term and, (I) long-term cohorts. J Fat mass in the short-term and (K) long-term cohorts. Sections of TA muscle were analysed using H&E staining in the long-term cohort for (L) quantification of fibre diameter and (M) ratio of centralised nuclei in control PolG^cont and PolG^mut mice, (PolG^cont n = 6, PolG^mut n = 5). TA muscle expression of genes associated with muscle growth and regeneration in the (N) short-term (PolG^cont n = 9, PolG^mut n = 10) and (O) long-term cohorts (PolG^cont n = 7, PolG^mut n = 4). F, H, J, n = 10/group; G, I, K: PolG^cont n = 9, PolG^mut n = 5). Data are presented as mean ± SEM, with P-value between control and mutant biological replicates determined by repeated measures two-way ANOVA with correction for multiple comparisons (F–K) or two-sided, unpaired two-tailed t-test (L) or Mann-Whitney test (A–C, E, M–O). Source data for these figures are provided in the Source Data file.