Chronology of mitochondrial and cellular events during skeletal muscle ischemia-reperfusion

Abstract

Peripheral artery disease (PAD) is a common circulatory disorder of the lower limb arteries that reduces functional capacity and quality of life of patients. Despite relatively effective available treatments, PAD is a serious public health issue associated with significant morbidity and mortality. Ischemia-reperfusion (I/R) cycles during PAD are responsible for insufficient oxygen supply, mitochondriopathy, free radical production, and inflammation and lead to events that contribute to myocyte death and remote organ failure. However, the chronology of mitochondrial and cellular events during the ischemic period and at the moment of reperfusion in skeletal muscle fibers has been poorly reviewed. Thus, after a review of the basal myocyte state and normal mitochondrial biology, we discuss the physiopathology of ischemia and reperfusion at the mitochondrial and cellular levels. First we describe the chronology of the deleterious biochemical and mitochondrial mechanisms activated by I/R. Then we discuss skeletal muscle I/R injury in the muscle environment, mitochondrial dynamics, and inflammation. A better understanding of the chronology of the events underlying I/R will allow us to identify key factors in the development of this pathology and point to suitable new therapies. Emerging data on mitochondrial dynamics should help identify new molecular and therapeutic targets and develop protective strategies against PAD.peripheral artery disease; ischemia-reperfusion; skeletal muscle; mitochondria; oxidative stress PERIPHERAL ARTERY DISEASE (PAD) refers to a common circulatory disorder of the lower limb caused by chronic narrowing of the arteries (e.g., stenosis and occlusion) or atherosclerosis. PAD represents a broad spectrum of disease severity, ranging from asymptomatic disease to frequent pain when walking (i.e., intermittent claudication or limping) or critical limb ischemia associated with decubitus pain and/or ulcers (114,126).PAD is known to be associated with reduced functional capacity and quality of life. It is a major cause of limb amputation, as well as an increased risk factor for myocardial infarction, stroke, and death. The incidence of PAD varies with age, from 3-10% in young people to 15-20% in people Ͼ70 yr of age, and is asymptomatic in 40% of the cases (1), with greater prevalence among men. The major PAD risk factors, including smoking, diabetes mellitus, dyslipidemia, hypertension, and obesity, are the same as those for cardiovascular and cerebrovascular diseases (35).Three main complementary treatment options improve the functional status and other clinical outcomes in PAD patients (54). 1) Optimization of medical therapy (i.e., pharmacotherapy) reduces the risk of cardiac ischemia, increases the distance a patient can walk, and improves the functional capacity of patients. 2) When possible, exercise training, a noninvasive and nonpharmacological therapy, improves walking ability and has protective effects in patients with PAD characterized by intermittent claudication and infrainguinal lesions...

Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

“…79 Altered skeletal muscle structural and metabolic properties magnify ischemiainduced functional impairment. 80, 81 Imaging studies with CT demonstrate that patients with PAD have a reduced calf muscle area that is not fully explained by inactivity.…”

Alternative Interventions to Prevent Oxidative Damage following Ischemia/Reperfusion

“…This increase triggers the activation of Na + /H + exchangers that consequently results in an increase in H + and changes the pH of the cell. These events impair the metabolic processes of the cell and affect K + channels in mitochondria [21, 23, 33, 64, 100, 101, 107–115]. …”

“…The efflux of H + produces an influx of Na + increasing the concentration of Na + in the cytosol. This increase activates the Na + /Ca +2 exchanger, which leads to an increase in cytosolic Ca +2 [21, 23, 33, 64, 100, 101, 107–115]. The high concentration of Ca +2 in the cytosol activates several proteases and other proteins that lead to dysfunction and destruction of organelle membranes and corruption of normal metabolism [21, 23, 33, 64, 100, 101, 107–115].…”

“…In the kidney, glomerular charge is inverted and overloads filtration solutes, increasing water, protein, and electrolyte loss through urine production. In hepatocytes, membrane potential and pH changes are detected, which suppress and activate many enzymes that optimally operate at a neutral pH, and lead to edema and necrosis [21, 23, 33, 64, 100, 101, 107–115]. …”

“…The high concentration of Ca +2 activates mitochondrial calcium-sensitive K + channels (mtKca) and mitochondrial nitric oxide synthase (mtNOS), which increases the levels of nitric oxide (NO • ) (Figure 3) [21, 23, 33, 64, 100, 101, 107–115]. NO • blocks complex IV in the respiratory chain, inducing an influx of electrons into the mitochondrial matrix and depletion of ATP.…”