Table.

Calf skeletal muscle pathology in peripheral artery disease

	Calf muscle pathologic changes in PAD	Associations with functional impairment and decline	Additional information or controversies
Computed tomography imaging	Greater leg ischemia is associated with smaller muscle area and greater fat infiltration.	Smaller muscle area and greater fat infiltration of calf muscle were associated with greater functional impairment and increased rates of mobility loss
Mitochondrial activity	Lower extremity ischemia is associated with reduced mitochondrial activity.	Reduced mitochondrial activity has been associated with poorer treadmill walking time but not with six-minute walk distance.	Data on the associations of mitochondrial activity with functional performance are mixed, with some studies showing a direct association and others showing no association.
Mitochondrial DNA damage	People with PAD have increased mitochondrial DNA mutations compared to those without PAD	Preliminary evidence shows that among people with PAD, those with lower mitochondrial copy number combined with lower mitochondrial DNA heteroplasmy have faster walking velocity.	Mitochondrial DNA damage was observed even in the unaffected leg of patients with unilateral PAD. However, the abundance of mitochondrial DNA damage was greater in the leg with ischemia.
Capillary density	Studies both show higher and lower capillary density in people with PAD. Greater capillary density may be a compensatory mechanism in PAD.	No association of capillary density and walking impairment has been demonstrated in people with PAD.	At least one study showing a lower capillary density in people with PAD compared to those without PAD was limited by a 12 year difference in age between those with vs. without PAD. Capillary density decreases with age in older people.
Histopathologic changes	Changes in myofiber typing are heterogeneous between people with PAD. Increases in type I and type II myofibers have been demonstrated in PAD. Leg ischemia is associated with changes of denervation. Larger myofibers have ‘holes’ that are devoid of mitochondrial activity, with evidence of autophagic marker accumulation in the holes. Central nuclei are also increased in muscle of people with PAD.	Larger myofibers are associated with faster walking velocity.	There is substantial heterogeneity in the relative abundance of type 1 vs. type 2 fibers in people with PAD.