Mitochondrial DNA damage in calf skeletal muscle and walking performance in people with peripheral artery disease.

Abstract Background Peripheral artery disease (PAD) is associated with mitochondrial dysfunction in calf skeletal muscle and a greater abundance of mitochondrial DNA (mtDNA) heteroplasmy. However, it is unknown whether calf skeletal muscle mtDNA of PAD participants harbors a greater abundance of mitochondrial DNA 4977-bp common deletion (mtDNA4977), strand breaks and oxidative damage (i.e., oxidized purines) compared to non-PAD participants and whether these mtDNA abnormalities are associated with poor walking performance in participants with PAD. Methods Calf muscle biopsies were obtained from 50 PAD participants (ankle-brachial index (ABI) Results Participants with PAD (mean age = 65.4 years, SD = 6.9; 14 (28%) women, 38 (76%) black) and without PAD (mean age = 65.2 years, SD = 6.7; 7 (28%) women, 16 (64%) black) did not differ in the abundance of calf muscle mtDNA4977 deletion, mtDNA strand breaks, and oxidized purines. Though, a greater abundance of mtDNA strand breaks within ND4/5 genes was significantly associated with poorer six-minute walk distance, lower usual-paced four-meter walking velocity, and lower fast-paced four-meter walking velocity in non-PAD participants. Significant associations were also found in the density of strand break damage (i.e., damage per mtDNA copy) within ND1/2, ND4/5 and COII/ATPase 6/8 region with six-minute walk distance, usual-paced four-meter walking velocity and fast-paced four-meter walking velocity in non-PAD participants. Significant interactions were found between PAD presence vs. absence and density of strand break damage within ND1/2, ND4/5, COII/ATPase 6/8 regions for the associations with six-minute walk distance, usual-paced four-meter walking velocity, fast-paced four-meter walking velocity. Conversely, of the three walking performance measures only the usual-paced four-meter walking velocity showed a significant, although modest, negative association with the abundance of oxidized purines in the D-Loop (P=0.031) and ND4/5 (P=0.033) regions in the calf skeletal muscle of people with PAD. Conclusion Overall, these data suggest that the abundance of calf muscle mtDNA strand breaks and mtDNA4977 common deletion are not associated with walking performance in people with PAD and may not be directly involved in the pathophysiology of PAD. Conversely, strand breaks in specific mtDNA regions may contribute to poor walking performance in people without PAD. Further study is needed to confirm whether usual-paced four-meter walking velocity is associated significantly with a greater abundance of oxidized purines in the D-loop, a “mutational hotspot” for oxidative damage, and why this association may differ from the association with six-minute walk distance and fast-paced four-meter walking velocity.