Abstract
BackgroundPatients with lower extremity peripheral artery disease (PAD) have decreased mobility, which is not fully explained by impaired blood supply to the lower limb. Additionally, reports are conflicted regarding fiber type distribution patterns in PAD, but agree that skeletal muscle mitochondrial respiration is impaired.MethodsTo test the hypothesis that reduced muscle fiber oxidative activity and type I distribution are negatively associated with walking performance in PAD, calf muscle biopsies from non-PAD (n = 7) and PAD participants (n = 26) were analyzed immunohistochemically for fiber type and size, oxidative activity, markers of autophagy, and capillary density. Data were analyzed using analysis of covariance.ResultsThere was a wide range in fiber type distribution among subjects with PAD (9–81 % type I fibers) that did not correlate with walking performance. However, mean type I fiber size correlated with 4-min normal- and fastest-paced walk velocity (r = 0.4940, P = 0.010 and r = 0.4944, P = 0.010, respectively). Although intensity of succinate dehydrogenase activity staining was consistent with fiber type, up to 17 % of oxidative fibers were devoid of mitochondria in their cores, and the core showed accumulation of the autophagic marker, LC3, which did not completely co-localize with LAMP2, a lysosome marker.ConclusionsCalf muscle type I fiber size positively correlates with walking performance in PAD. Accumulation of LC3 and a lack of co-localization of LC3 with LAMP2 in the area depleted of mitochondria in PAD fibers suggests impaired clearance of damaged mitochondria, which may contribute to reduced muscle oxidative capacity. Further study is needed to determine whether defective mitophagy is associated with decline in function over time, and whether interventions aimed at preserving mitochondrial function and improving autophagy can improve walking performance in PAD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1030-6) contains supplementary material, which is available to authorized users.
Highlights
Patients with lower extremity peripheral artery disease (PAD) have decreased mobility, which is not fully explained by impaired blood supply to the lower limb
But not fiber type distribution, relates to walking performance in subjects with PAD Quantifying the relative abundance of type I, IIa and IIx fibers showed that PAD participants exhibited trends toward greater mean frequency of hybrid type IIa/x fibers (P = 0.058) and reduced frequency of IIa fibers (P = 0.088), but had a similar mean frequency of type I fibers compared to non-PAD participants (Fig. 1A)
Non-PAD subjects exhibited a relatively even fiber type distribution, typical of healthy muscle, whereas PAD subjects demonstrated a wide heterogeneity of fiber type distributions
Summary
Patients with lower extremity peripheral artery disease (PAD) have decreased mobility, which is not fully explained by impaired blood supply to the lower limb. Patients with lower extremity peripheral artery disease (PAD), caused by atherosclerosis in the lower extremities, have faster functional decline and higher rates of mobility loss compared to people without PAD [1,2,3,4,5,6,7]. Patients with PAD experience ischemia of lower limb skeletal muscle during walking activity, when metabolic demands exceed oxygen supply, followed by reperfusion during rest. While bypass surgery improves walking performance in PAD patients [17], it is associated with a higher degree of morbidity and mortality, and patients may later require additional procedures with a greater risk of limb loss [18]. Alternative strategies, perhaps targeting mitochondrial health, may be advantageous targets of future therapies for PAD patients
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