Mitochondriopathy of Peripheral Arterial Disease

Abstract

The signs and symptoms of peripheral arterial occlusive disease (PAD), including claudication, rest pain, and tissue loss, are consequences of compromised bioenergetics and oxidative tissue injury within the affected lower extremities. Compromised bioenergetics is the result of a combination of low blood flow through diseased arteries and diminished adenosine triphosphate production by dysfunctional mitochondria. The tissue injury appears to be secondary to increased production of reactive oxygen species by dysfunctional mitochondria and by inflammation, in association with ischemia and ischemia/reperfusion. In this review, we present the current histomorphologic, physiologic, and biochemical evidence defining the nature of this mitochondriopathy and discuss its contribution to the pathogenesis and clinical manifestations of PAD.

Chronically ischemic mouse skeletal muscle exhibits myopathy in association with mitochondrial dysfunction and oxidative damage

“…The ischemia-reperfusion of every bout of claudication increases oxidative stress, triggers inflammation and oxidative damage to the tissues (4,5,12,13,22,23), and initiates mitochondrial injury and dysfunction (4,5,22,23). Mitochondrial dysfunction can then be perpetuated by repeated destructive cycles of ischemia-reperfusion, causing amplification of respiratory chain defects, compromised bioenergetics, increased ROS production, diminished MnSOD antioxidant activity, and oxidative stress (5,17). In this process, mitochondrial biogenesis may be induced as the ischemic muscle attempts to compensate for its compromised bioenergetic state.…”

“…Defective mitochondria are central to this myopathy through compromised performance as primary energy producers and regulators of oxygen radical species, contributing to a progressive deterioration in muscle function and microanatomy (4,5,17,22,23). PAD myopathy is characterized by an increased content of dysfunctional mitochondria having significant defects in electron transport chain (ETC) complexes I, III, and IV (17,24).…”

“…PAD myopathy is characterized by an increased content of dysfunctional mitochondria having significant defects in electron transport chain (ETC) complexes I, III, and IV (17,24). These defects are associated with a bioenergetic decline, characterized by inadequate oxidative phosphorylation, decreased ATP energy production, and increased oxidative stress (4,5,17,(23)(24)(25). All start with inflow arterial occlusions, which produce low blood supply and myopathy (due to ischemic injury), and the two, in conjunction, produce the manifestations of PAD claudication (5,14,22,23).…”

Skeletal Muscle Mitochondrial Function in Peripheral Arterial Disease: Usefulness of Muscle Biopsy

“…Experimental data show that skeletal muscle responds to inflow arterial occlusion with the development of myopathic histological changes, a drop in total protein content, and a trend toward decreased wet weight (Makris, et al, 2007 ;Pipinos, et al, 2008b). Peripheral arterial disease is characterized by a significant increase in the mitochondrial content of skeletal muscle, and mitochondrial proliferation is characteristic of mitochondrial diseases and aging (Levak-Frank et al, 1995;Wallace, 2000;Wredenberg et al, 2002;Makris et al, 2007;Pipinos et al, 2008b). In skeletal muscle, an upregulation of mitochondrial biogenesis may be associated with and alteration of muscle fibre type toward the more oxidative type I and IIa fibres (Pipinos et al, 2008b).…”

“…Peripheral arterial disease is a consequence of compromised blood supply to the ischemic limb (Brass, 1996;Brass & Hiatt, 2000). Experimental data show that skeletal muscle responds to inflow arterial occlusion with the development of myopathic histological changes, a drop in total protein content, and a trend toward decreased wet weight (Makris, et al, 2007 ;Pipinos, et al, 2008b). Peripheral arterial disease is characterized by a significant increase in the mitochondrial content of skeletal muscle, and mitochondrial proliferation is characteristic of mitochondrial diseases and aging (Levak-Frank et al, 1995;Wallace, 2000;Wredenberg et al, 2002;Makris et al, 2007;Pipinos et al, 2008b).…”