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Extensive skeletal muscle cell mitochondriopathy distinguishes critical limb ischemia patients from claudicants
Terence E. Ryan, … , Espen E. Spangenburg, Joseph M. McClung
Terence E. Ryan, … , Espen E. Spangenburg, Joseph M. McClung
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e123235. https://doi.org/10.1172/jci.insight.123235.
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Research Article Metabolism

Extensive skeletal muscle cell mitochondriopathy distinguishes critical limb ischemia patients from claudicants

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Abstract

The most severe manifestation of peripheral arterial disease (PAD) is critical limb ischemia (CLI). CLI patients suffer high rates of amputation and mortality; accordingly, there remains a clear need both to better understand CLI and to develop more effective treatments. Gastrocnemius muscle was obtained from 32 older (51–84 years) non-PAD controls, 27 claudicating PAD patients (ankle-brachial index [ABI] 0.65 ± 0.21 SD), and 19 CLI patients (ABI 0.35 ± 0.30 SD) for whole transcriptome sequencing and comprehensive mitochondrial phenotyping. Comparable permeabilized myofiber mitochondrial function was paralleled by both similar mitochondrial content and related mRNA expression profiles in non-PAD control and claudicating patient tissues. Tissues from CLI patients, despite being histologically intact and harboring equivalent mitochondrial content, presented a unique bioenergetic signature. This signature was defined by deficits in permeabilized myofiber mitochondrial function and a unique pattern of both nuclear and mitochondrial encoded gene suppression. Moreover, isolated muscle progenitor cells retained both mitochondrial functional deficits and gene suppression observed in the tissue. These findings indicate that muscle tissues from claudicating patients and non-PAD controls were similar in both their bioenergetics profile and mitochondrial phenotypes. In contrast, CLI patient limb skeletal muscles harbor a unique skeletal muscle mitochondriopathy that represents a potentially novel therapeutic site for intervention.

Authors

Terence E. Ryan, Dean J. Yamaguchi, Cameron A. Schmidt, Tonya N. Zeczycki, Saame Raza Shaikh, Patricia Brophy, Thomas D. Green, Michael D. Tarpey, Reema Karnekar, Emma J. Goldberg, Genevieve C. Sparagna, Maria J. Torres, Brian H. Annex, P. Darrell Neufer, Espen E. Spangenburg, Joseph M. McClung

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Figure 2

Histological assessment of skeletal muscle specimens.

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Histological assessment of skeletal muscle specimens.
Skeletal muscle bi...
Skeletal muscle biopsy specimens were obtained from the gastrocnemius of healthy adults (HA), intermittent claudicants (IC), and critical limb ischemia (CLI) patients. (A) Histological (H&E staining) assessment and immunofluorescent staining for dystrophin confirms that samples obtained were not from necrotic regions within the limb (note: color differences in IC samples are due to paraffin embedding). Small white arrows indicate evidence of small, irregularly shaped myofibers in IC and CLI patients. (B) Distribution plots of myofiber cross-sectional area from each patient group (N = 3 for HA, N = 8 for IC, N = 6 for CLI). (C) Quantification of mean myofiber cross-sectional area (N = 3 for HA, N = 8 for IC, N = 6 for CLI). (D) Representative immunofluorescence images stained for myosin heavy chain (MyHC) type I (slow twitch myofibers). (E) Quantification of the percentage of type I myofibers in each group (N = 3 for HA, N = 7 for IC, N = 6 for CLI). **P < 0.01 using ANOVA with Tukey’s multiple comparison test. NS, not significant. Data are presented as the mean ± SEM.

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