NF‐kappa B signaling and skeletal muscle fiber atrophy: a rodent model of exercise with restricted blood supply, and Peripheral Arterial Disease patients

Reduced mechanical loading during bedrest, spaceflight, and casting, causes rapid morphological changes in skeletal muscle: fiber atrophy and reduction of slow-twitch fibers. An emerging signaling event in response to unloading is the translocation of neuronal nitric oxide synthase (nNOSμ) from the sarcolemma to the cytosol. We used EUK-134, a cell-permeable mimetic of superoxide dismutase and catalase, to test the role of redox signaling in nNOSμ translocation and muscle fiber atrophy as a result of short-term (54 h) hindlimb unloading. Fischer-344 rats were divided into ambulatory control, hindlimb-unloaded (HU), and hindlimb-unloaded + EUK-134 (HU-EUK) groups. EUK-134 mitigated the unloading-induced phenotype, including muscle fiber atrophy and muscle fiber-type shift from slow to fast. nNOSμ immunolocalization at the sarcolemma of the soleus was reduced with HU, while nNOSμ protein content in the cytosol increased with unloading. Translocation of nNOS from the sarcolemma to cytosol was virtually abolished by EUK-134. EUK-134 also mitigated dephosphorylation at Thr-32 of FoxO3a during HU. Hindlimb unloading elevated oxidative stress (4-hydroxynonenal) and increased sarcolemmal localization of Nox2 subunits gp91phox (Nox2) and p47phox, effects normalized by EUK-134. Thus, our findings are consistent with the hypothesis that oxidative stress triggers nNOSμ translocation from the sarcolemma and FoxO3a dephosphorylation as an early event during mechanical unloading. Thus, redox signaling may serve as a biological switch for nNOS to initiate morphological changes in skeletal muscle fibers.

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Prognostic review and time-to-event data meta-analysis of low skeletal muscle mass in patients with peripheral arterial disease of the lower limbs undergoing revascularization

International Angiology ◽

10.23736/s0392-9590.19.04248-2 ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Madeleine Sharpe ◽

Emeka Okoye ◽

George A. Antoniou

Keyword(s):

Skeletal Muscle ◽

Peripheral Arterial Disease ◽

Skeletal Muscle Mass ◽

Meta Analysis ◽

Arterial Disease ◽

Lower Limbs ◽

Event Data ◽

Time To Event ◽

Time To Event Data ◽

Peripheral Arterial

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Skeletal muscle phenotype is associated with exercise tolerance in patients with peripheral arterial disease

Yearbook of Vascular Surgery ◽

10.1016/s0749-4041(08)70366-x ◽

2007 ◽

Vol 2007 ◽

pp. 32-33

Author(s):

C.K. Ozaki

Keyword(s):

Skeletal Muscle ◽

Peripheral Arterial Disease ◽

Exercise Tolerance ◽

Arterial Disease ◽

Peripheral Arterial

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Abstract 3321: Gender Impacts Capillary Density and Skeletal Muscle Composition in Patients With Peripheral Arterial Disease

Circulation ◽

10.1161/circ.116.suppl_16.ii_748-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

William S Jones ◽

Brian D Duscha ◽

Jennifer L Robbins ◽

Amy J Aldrich ◽

Judy G Regensteiner ◽

...

Keyword(s):

Skeletal Muscle ◽

Gender Differences ◽

Endothelial Cells ◽

Muscle Fiber ◽

Fiber Type ◽

Capillary Density ◽

Arterial Disease ◽

Healthy Controls ◽

Muscle Composition ◽

Peripheral Arterial

Background : Peripheral arterial disease (PAD) is a disorder characterized by impaired blood flow to the legs and maladaptive changes in the skeletal muscle. It is generally accepted that the skeletal muscle characteristics in patients with PAD include decreased capillary density and an altered percentage of oxidative myofibers. The scientific literature is conflicting, and it is based on studies with small sample size and older methodologies of skeletal muscle analysis. In addition, women are under-represented or not included at all in these studies. Hypothesis : We hypothesized that there would be differences in skeletal muscle composition in PAD patients compared to healthy controls. We further hypothesized that there would be gender differences in skeletal muscle composition in PAD patients versus healthy controls. Methods : Thirty -one patients with PAD and 31 age-, gender-, and activity-matched healthy controls underwent gastrocnemius muscle biopsy. Capillary density analysis and muscle fiber type determination were performed using immunohistochemistry techniques. Capillary density was measured as endothelial cells per muscle fiber and endothelial cells per area (mm 2 ). Results : There was no significant difference in capillary density in patients with PAD versus healthy controls when measured as endothelial cells per fiber (mean = 1.45 ± 0.43 vs. 1.50 ± 0.35, NS) or area (mean = 1.20 ± 0.29 vs. 1.29 ± 0.33, NS). There was also no difference in muscle fiber type composition between the groups. In the PAD cohort, capillary density was significantly lower in the men versus the women (mean = 1.36 ± 0.35 vs. 1.59 ± 0.51, p=0.005). In our cohort of women, there was no difference in capillary density in patients with PAD versus healthy controls (N=12). In men, capillary density was significantly lower in the PAD group versus healthy controls (N=19, mean = 1.09 ± 0.20 vs. 1.28 ± 0.34, p=0.043). Conclusions : Our data fail to confirm the belief that patients with PAD have a decreased capillary density and an altered percentage of oxidative myofibers. However, we did find that gender has an important impact on these characteristics. Further study of skeletal muscle composition in PAD may help to better understand the functional relevance of the gender differences.

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