The myopathy of peripheral arterial occlusive disease: Part 2. Oxidative stress, neuropathy, and shift in muscle fiber type

Abstract

In recent years, an increasing number of studies have demonstrated that a myopathy is present, contributes, and, to a certain extent, determines the pathogenesis of peripheral arterial occlusive disease. These works provide evidence that a state of repetitive cycles of exercise-induced ischemia followed by reperfusion at rest operates in patients with peripheral arterial occlusive disease and mediates a large number of structural and metabolic changes in the muscle, resulting in reduced strength and function. The key players in this process appear to be defective mitochondria that, through multilevel failure in their roles as energy, oxygen radical species, and apoptosis regulators, produce and sustain a progressive decline in muscle performance. In this 2-part review, the currently available evidence that characterizes the nature and mechanisms responsible for this myopathy is highlighted. In part 1, the functional and histomorphological characteristics of the myopathy were reviewed, and the main focus was on the biochemistry and bioenergetics of its mitochondriopathy. In part 2, accumulating evidence that oxidative stress related to ischemia reperfusion is probably the major operating mechanism of peripheral arterial occlusive disease myopathy is reviewed. Important new findings of a possible neuropathy and a shift in muscle fiber type are also reviewed. Learning more about these mechanisms will enhance our understanding of the degree to which they are preventable and treatable.

Figure 1.

Skeletal muscle structure and mitochondria. Skeletal muscles are made up of muscle cells or myofibers. Each individual myofiber is covered by a plasma membrane (sarcolemma) and contains multiple nuclei located immediately beneath the sarcolemma. Myofibers contain a large number of myofibrils that collectively make up the contractile components of the muscle. The myofibrils are surrounded by large numbers of mitochondria also known as powerhouses of the cell because their primary role is the generation of bioenergy in the form of adenosine triphosphate. Mitochondria contain a compact mitochondrial genome, their own class of ribosomes and a series of structural, regulatory, and functional proteins involved in a variety of critical tasks ranging from bioenergetic pathways (oxidative phosphorylation, respiration, Krebs cycle, and fatty acid oxidation), intercellular communication and cell death pathways (redox signalling through oxygen radical species and apoptotic progression), nucleotide transport, and biosynthesis of mitochondrial components.

Figure 2.

Mitochondrial theory of degenerative diseases and aging. Dysfunction in the electron transport chain leads to decreased ATP production and compromised cellular bioenergetics and increased production of reactive oxygen species. The ROS cause damage to mitochondrial DNA, proteins, and lipids, launching a vicious cycle of worsening electron transport chain disruption, oxidant production, and further mitochondrial deterioration. ATP indicates adenosine triphosphate; ROS, reactive oxygen species.

Figure 3.

Sources of reactive oxygen species and major antioxidant mechanisms. The source of ROS in patients with arterial disease can be dysfunctional mitochondria, activated neutrophils, or xanthine oxidase. The primary enzymatic antioxidant defenses are SOD, GPX, and catalase, each of which is capable of neutralizing oxidants or transforming them to less reactive species. Reduced GSH is a major antioxidant that provides reducing equivalents to GPX becoming in the process as GSSG. In mammalian skeletal muscle, 2 isoforms of superoxide dismutase exist, Cu-ZnSOD and MnSOD, named for the metal cofactors bound to their active site. These isoforms differ in their cellular location, with Cu-ZnSOD primarily located in the cytosol and MnSOD localized to the mitochondria. There is significant evidence to suggest that antioxidant defenses are compromised in arterial disease patients contributing to increased oxidative stress and injury in the chronically ischemic limbs. ROS indicates reactive oxygen species; SOD, superoxide dismutase; GPX, glutathione peroxidase; GSH, glutathione; GSSG, oxidized glutathione; NADPH, nicotinamide adenosine dinucleotide phosphate, reduced form.

Figure 4.

Reactive oxygen species in peripheral arterial disease. The mitochondrial ETC, activated neutrophils, and xanthine oxidase are the most likely sources of ROS in patients with peripheral arterial disease. The ROS can damage every structure in the myocytes including contractile elements, mitochondria, and other organelles. Furthermore, they can be injurious to the nerves, skin, and subcutaneous tissues of peripheral arterial occlusive disease limbs. Claudication, rest pain, and tissue loss find their place in the heart of this continuum of events, coming into view as the external manifestations of ongoing tissue injury and deterioration. ETC indicates electron transport chain; ROS, reactive oxygen species; NADPH, nicotinamide adenosine dinucleotide phosphate, reduced form.

Figure 5.

Proposed pathway for the pathogenesis of PAD manifestations. The fundamental problem in PAD is obviously the presence of arterial occlusive disease. Arterial stenoses and occlusions produce effort-induced cycles of ischemia and reperfusion. These cycles initiate a combination of oxidative stress and inflammation, which sets in motion a cascade of injury to muscle cells and their organelles along with cellular apoptosis and necrosis. Key players in the chronic phase of this process are dysfunctional mitochondria that, through multilevel failure in their roles as energy, oxygen radical species, and apoptosis regulators, produce and sustain a myopathy with progressive decline in muscle performance. This myopathy is the better explored component of this process in PAD limbs, and its nature is the main focus of the present review. However, there is increasing evidence demonstrating that the injury route expands to involve every structure in the leg including nerves, skin, and subcutaneous tissues. Claudication, rest pain, and tissue loss then emerge as the external manifestations of ongoing tissue functional deterioration and injury. PAD indicates peripheral arterial occlusive disease; ETC, electron transport chain.