Abnormal myofiber morphology and limb dysfunction in claudication

Koutakis, Panagiotis; Myers, Sara A.; Cluff, Kim; Ha, Duy M.; Haynatzki, Gleb; McComb, Rodney D.; Uchida, Koji; Miserlis, Dimitrios; Papoutsi, Evlampia; Johanning, Jason M.; Casale, George P.; Pipinos, Iraklis I.

doi:10.1016/j.jss.2015.02.011

Cited by 65 publications

(63 citation statements)

References 37 publications

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“…Our present finding of myofiber atrophy (Figure 2) in demand ischemia has been observed in limb muscle biopsies from PAD patients [28]. Altered myofiber morphology has been correlated with diminished calf muscle strength and reduced maximum walking distance [4]. Increased protease activities have been implicated in muscle wasting in claudicating PAD patients undergoing supervised exercise [8].…”

Section: Discussionmentioning

confidence: 59%

“…In PAD patients, muscle degeneration as well as vascular and mitochondrial dysfunctions are associated with evidence of increased inflammation [3] and oxidative stress which may contribute to limb dysfunction [4]. In patients with diabetes or the metabolic syndrome, muscle tissue remodeling becomes defective due to the deleterious microenvironment manifested by muscle degeneration, fatty infiltration, inflammation, and diminished angiogenic capacity [5].…”

Section: Introductionmentioning

confidence: 99%

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Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice

Albadawi

Tzika

Rask‐Madsen

et al. 2016

Journal of Surgical Research

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Background Obesity and type 2 diabetes are major risk factors for peripheral arterial disease (PAD) in humans which can result in lower limb demand ischemia and exercise intolerance. Exercise triggers skeletal muscle adaptation including increased vasculogenesis. The goal of this study was to determine whether demand ischemia modulates revascularization, fiber size, and signaling pathways in the ischemic hind limb muscles of mice with diet-induced obesity (DIO). Materials and Methods DIO mice (n=7) underwent unilateral femoral artery ligation (FAL) and recovered for 2-weeks followed by 4-weeks with daily treadmill exercise to induce demand ischemia. A parallel sedentary ischemia group (n=7) had FAL without exercise. The contralateral limb muscles of sedentary ischemia served as control. Muscles were examined for capillary density, myofiber cross-sectional area (CSA), cytokine levels, and phosphorylation of STAT3 and ERK1/2. Results Exercise significantly enhanced capillary density (p<0.01) and markedly lowered CSA (p<0.001) in demand ischemia compared to sedentary ischemia. These findings coincided with a significant increase in G-CSF (p<0.001) and IL-7 (p<0.01) levels. In addition, phosphorylation of STAT3 and ERK1/2 (p<0.01) were increased while UCP-1 and MCP-1 protein levels were lower (p<0.05) without altering VEGF and TNFα protein levels. Demand ischemia increased the PGC1α mRNA (p<0.001) without augmenting PGC1α protein levels. Conclusions Exercise induced limb demands ischemia in the setting of DIO causes myofiber atrophy despite an increase in muscle capillary density. The combination of persistent increase in TNFα, lower VEGF and failure to increase PGC1α protein may reflect a deficient adaption to demand ischemia in DIO.

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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice

Albadawi

Tzika

Rask‐Madsen

et al. 2016

Journal of Surgical Research

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“…87 Evidence of myofiber damage is associated with both reduced walking distance and muscle strength in patients with claudication. 99 Further, altered regulation of a cytoskeletal protein, desmin, is associated with reduced mitochondrial respiratory function and functional capacity in PAD. 100 There is evidence of inadequate mitochondrial clearance through autophagy in the skeletal muscle in PAD that associates with walking parameters, consistent with increased mitochondrial damage.…”

Section: Vascular Dysfunction In Padmentioning

confidence: 99%

Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

Hamburg

Creager

2017

Circ J

157

124

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estimates a more than 30% increase in deaths and disability attributable to PAD between 2005 and 2015, which is largely determined by population aging. 3,12 PAD prevalence escalates with advancing age, affecting 1 in 10 adults older than 70 years. In addition to age, smoking and diabetes are the strongest risk factors for PAD across the world. A comprehensive global evaluation of PAD found that its prevalence and risk factors are similar in high-income countries to low-and middle-income countries. 2,13 Lower socioeconomic status is a newly recognized risk factor for PAD. 14 Importantly, there has been a greater increase in PAD prevalence in low-and middle-income countries, rising by 28.7% from 2000 to 2010 as compared with 13.1% in high-income countries. 2, 15 The changing burden of PAD is also greater in women as compared with men.The health implications of PAD derive from both its limb and cardiovascular manifestations. Consistent with the systemic nature of atherosclerosis, polyvascular disease is common in patients with PAD. 16 In the REACH registry, 61% of PAD patients had concomitant coronary artery disease (CAD) and/or cerebrovascular disease. 16 Thus, the presence of PAD portends a high risk for subsequent cardiovascular events. A meta-analysis of over 48,000 participants in population-based cohort studies demonstrated that a low ankle-brachial index (ABI) predicted a 2-fold risk of death, cardiovascular death, and major coronary events at all ranges of the Framingham Risk Score. 4 Further, the elevated risk of cardiovascular events is present in both symptomatic and asymptomatic patients. 17 Patients with atherosclerotic disease in more than 1 vascular territory have particularly poor outcomes. 6 In the over 5,000 Japanese T here is growing recognition of the effect of peripheral artery disease (PAD) on cardiovascular health. 1 Recent studies indicate that, globally, over 200 million adults have PAD, 2,3 which is an expression of systemic atherosclerosis and well-established as heightening the risk for cardiovascular events. 4-6 The limb manifestations of PAD induce considerable suffering. Patients with PAD experience intermittent claudication, characterized as exertional leg pain that limits walking ability, and often times, disability. 7-9 Current medical therapies to reduce the burden of lower extremity symptoms in patients with PAD are limited. Revascularization by endovascular intervention or surgical reconstruction is used to treat lifestyle-limiting claudication if patients do not respond adequately to medical therapy including exercise training. Indeed, lower extremity revascularization with endovascular approaches has undergone a dramatic increase in use. 10 Though endovascular therapy improves blood flow and function, there are significant associated risks, and durability may be limited, especially in infrainguinal disease. Abundant evidence demonstrates the benefits of exercise therapy in claudication, yet the mechanisms underlying the beneficial effects remain incompletely defined. 11 Thus, ...

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“…Candidate myofibers were identified by morphological characteristics that are present in PAD myopathy (abnormal myofiber shapes, irregular clustering, and group atrophy). These characteristics were quantified in our previous studies, and correlated with the progression of the disease (8, 22). Figure 1 displays the morphological changes skeletal muscle undergoes with increasing PAD severity.…”

Section: Methodsmentioning

confidence: 99%

Analysis of ischemic muscle in patients with peripheral artery disease using X-ray spectroscopy

Becker

Cluff

Duraisamy

et al. 2017

Journal of Surgical Research

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Background Peripheral artery disease (PAD) is a vascular disease caused by atherosclerosis resulting in decreased blood flow to the lower extremities. The ankle brachial index (ABI) is a standard PAD diagnostic test, but only identifies reduced blood flow based on blood pressure differences. The early signs of PAD manifest themselves not only clinically, but also at an elemental and biochemical level. However, the biochemical and elemental alterations to PAD muscle are not well understood. The objective of this study was to compare fundamental changes in intracellular elemental compositions between control, claudicating, and critical limb ischemia muscle tissue. Materials and methods Gastrocnemius biopsies from three subjects including one control (ABI≥0.9), one claudicating (0.4≤ABI<0.9) and one critical limb ischemia patient (ABI<0.4) were evaluated using a scanning electron microscope and energy dispersive X-ray spectroscopy to quantify differences in elemental compositions. Spectra were collected for 5 myofibers per specimen. An analysis of variance was performed to identify significant differences in muscle elemental compositions. Results This study revealed that intracellular magnesium and calcium were lower in PAD compared to control myofibers while sulfur was higher. Magnesium and calcium are antagonistic, meaning, if magnesium concentrations go down calcium concentrations should go up. However, our findings do not support this antagonism in PAD. Our analysis found decreases in sodium and potassium, in PAD myofibers. Conclusions These findings may provide insight into the pathologic mechanisms that may operate in ischemic muscle and aid in the development of specialized preventive and rehabilitative treatment plans for PAD patients.

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Abnormal myofiber morphology and limb dysfunction in claudication

Cited by 65 publications

References 37 publications

Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice

Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice

Pathophysiology of Intermittent Claudication in Peripheral Artery Disease

Analysis of ischemic muscle in patients with peripheral artery disease using X-ray spectroscopy

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