Walking performance is positively correlated to calf muscle fiber size in peripheral artery disease subjects, but fibers show aberrant mitophagy: an observational study

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Abstract

Background

Patients with lower extremity peripheral artery disease (PAD) have decreased mobility, which is not fully explained by impaired blood supply to the lower limb. Additionally, reports are conflicted regarding fiber type distribution patterns in PAD, but agree that skeletal muscle mitochondrial respiration is impaired.

Methods

To test the hypothesis that reduced muscle fiber oxidative activity and type I distribution are negatively associated with walking performance in PAD, calf muscle biopsies from non-PAD (n = 7) and PAD participants (n = 26) were analyzed immunohistochemically for fiber type and size, oxidative activity, markers of autophagy, and capillary density. Data were analyzed using analysis of covariance.

Results

There was a wide range in fiber type distribution among subjects with PAD (9–81 % type I fibers) that did not correlate with walking performance. However, mean type I fiber size correlated with 4-min normal- and fastest-paced walk velocity (r = 0.4940, P = 0.010 and r = 0.4944, P = 0.010, respectively). Although intensity of succinate dehydrogenase activity staining was consistent with fiber type, up to 17 % of oxidative fibers were devoid of mitochondria in their cores, and the core showed accumulation of the autophagic marker, LC3, which did not completely co-localize with LAMP2, a lysosome marker.

Conclusions

Calf muscle type I fiber size positively correlates with walking performance in PAD. Accumulation of LC3 and a lack of co-localization of LC3 with LAMP2 in the area depleted of mitochondria in PAD fibers suggests impaired clearance of damaged mitochondria, which may contribute to reduced muscle oxidative capacity. Further study is needed to determine whether defective mitophagy is associated with decline in function over time, and whether interventions aimed at preserving mitochondrial function and improving autophagy can improve walking performance in PAD.

Electronic supplementary material

The online version of this article (doi:10.1186/s12967-016-1030-6) contains supplementary material, which is available to authorized users.

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Most cited references 46

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Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability.

J M Guralnik, L Ferrucci, E Simonsick … (1995)

Functional assessment is an important part of the evaluation of elderly persons. We conducted this study to determine whether objective measures of physical function can predict subsequent disability in older persons. This prospective cohort study included men and women 71 years of age or older who were living in the community, who reported no disability in the activities of daily living, and who reported that they were able to walk one-half mile (0.8 km) and climb stairs without assistance. The subjects completed a short battery of physical-performance tests and participated in a follow-up interview four years later. The tests included an assessment of standing balance, a timed 8-ft (2.4-m) walk at a normal pace, and a timed test of five repetitions of rising from a chair and sitting down. Among the 1122 subjects who were not disabled at base line and who participated in the four-year follow-up, lower scores on the base-line performance tests were associated with a statistically significant, graduated increase in the frequency of disability in the activities of daily living and mobility-related disability at follow-up. After adjustment for age, sex, and the presence of chronic disease, those with the lowest scores on the performance tests were 4.2 to 4.9 times as likely to have disability at four years as those with the highest performance scores, and those with intermediate performance scores were 1.6 to 1.8 times as likely to have disability. Among nondisabled older persons living in the community, objective measures of lower-extremity function were highly predictive of subsequent disability. Measures of physical performance may identify older persons with a preclinical stage of disability who may benefit from interventions to prevent the development of frank disability.

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Peripheral arterial disease detection, awareness, and treatment in primary care.

Alan Hirsch (2001)

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis that is common and is associated with an increased risk of death and ischemic events, yet may be underdiagnosed in primary care practice. To assess the feasibility of detecting PAD in primary care clinics, patient and physician awareness of PAD, and intensity of risk factor treatment and use of antiplatelet therapies in primary care clinics. The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program, a multicenter, cross-sectional study conducted at 27 sites in 25 cities and 350 primary care practices throughout the United States in June-October 1999. A total of 6979 patients aged 70 years or older or aged 50 through 69 years with history of cigarette smoking or diabetes were evaluated by history and by measurement of the ankle-brachial index (ABI). PAD was considered present if the ABI was 0.90 or less, if it was documented in the medical record, or if there was a history of limb revascularization. Cardiovascular disease (CVD) was defined as a history of atherosclerotic coronary, cerebral, or abdominal aortic aneurysmal disease. Frequency of detection of PAD; physician and patient awareness of PAD diagnosis; treatment intensity in PAD patients compared with treatment of other forms of CVD and with patients without clinical evidence of atherosclerosis. PAD was detected in 1865 patients (29%); 825 of these (44%) had PAD only, without evidence of CVD. Overall, 13% had PAD only, 16% had PAD and CVD, 24% had CVD only, and 47% had neither PAD nor CVD (the reference group). There were 457 patients (55%) with newly diagnosed PAD only and 366 (35%) with PAD and CVD who were newly diagnosed during the survey. Eighty-three percent of patients with prior PAD were aware of their diagnosis, but only 49% of physicians were aware of this diagnosis. Among patients with PAD, classic claudication was distinctly uncommon (11%). Patients with PAD had similar atherosclerosis risk factor profiles compared with those who had CVD. Smoking behavior was more frequently treated in patients with new (53%) and prior PAD (51%) only than in those with CVD only (35%; P <.001). Hypertension was treated less frequently in new (84%) and prior PAD (88%) only vs CVD only (95%; P <.001) and hyperlipidemia was treated less frequently in new (44%) and prior PAD (56%) only vs CVD only (73%, P<.001). Antiplatelet medications were prescribed less often in patients with new (33%) and prior PAD (54%) only vs CVD only (71%, P<.001). Treatment intensity for diabetes and use of hormone replacement therapy in women were similar across all groups. Prevalence of PAD in primary care practices is high, yet physician awareness of the PAD diagnosis is relatively low. A simple ABI measurement identified a large number of patients with previously unrecognized PAD. Atherosclerosis risk factors were very prevalent in PAD patients, but these patients received less intensive treatment for lipid disorders and hypertension and were prescribed antiplatelet therapy less frequently than were patients with CVD. These results demonstrate that underdiagnosis of PAD in primary care practice may be a barrier to effective secondary prevention of the high ischemic cardiovascular risk associated with PAD.

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Lower extremity function and subsequent disability: consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery.

J M Guralnik, L Ferrucci, C F Pieper … (2000)

Although it has been demonstrated that physical performance measures predict incident disability in previously nondisabled older persons, the available data have not been fully developed to create usable methods for determining risk profiles in community-dwelling populations. Using several populations and different follow-up periods, this study replicates previous findings by using the Established Populations for the Epidemiologic Study of the Elderly (EPESE) performance battery and provides equations for the prediction of disability risk according to age, sex, and level of performance. Tests of balance, time to walk 8 ft, and time to rise from a chair 5 times were administered to 4,588 initially nondisabled persons in the four sites of the EPESE and to 1,946 initially nondisabled persons in the Hispanic EPESE. Follow-up assessment for activity of daily living (ADL) and mobility-related disability occurred from 1 to 6 years later. In the EPESE, compared with those with the best performance (EPESE summary performance score of 10-12), the relative risks of mobility-related disability for those with scores of 4-6 ranged from 2.9 to 4.9 and the relative risk of disability for those with scores of 7-9 ranged from 1.5 to 2.1, with similar consistent results for ADL disability. The observed rates of incident disability according to performance level in the Hispanic EPESE agreed closely with rates predicted from models developed from the EPESE sites. Receiver operating characteristic curves showed that gait speed alone performed almost as well as the full battery in predicting incident disability. Performance tests of lower extremity function accurately predict disability across diverse populations. Equations derived from models using both the summary score and the gait speed alone allow for the estimation of risk of disability in community-dwelling populations and provide valuable information for estimating sample size for clinical trials of disability prevention.

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Author and article information

Contributors

Sarah H. White:

ORCID: http://orcid.org/0000-0002-1449-8837

shwhite@tamu.edu

Mary M. McDermott: (312) 503-6400 , mdm608@northwestern.edu

Robert L. Sufit: r-sufit@northwestern.edu

Kate Kosmac: kate.kosmac@uky.edu

Alex W. Bugg: awbu223@uky.edu

Marta Gonzalez-Freire: marta.gonzalezfreire@nih.gov

Luigi Ferrucci: ferruccilu@grc.nia.nih.gov

Lu Tian: lutian@stanford.edu

Lihui Zhao: Lihui.zhao@northwestern.edu

Ying Gao: ying.gao@northwestern.edu

Melina R. Kibbe: mkibbe@northwestern.edu

Michael H. Criqui: mcriqui@ucsd.edu

Christiaan Leeuwenburgh: cleeuwen@ufl.edu

Charlotte A. Peterson: (859) 218-0476 , cpete4@uky.edu

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 29 September 2016

Publication date PMC-release: 29 September 2016

Publication date Collection: 2016

Volume: 14

Electronic Location Identifier: 284

Affiliations

[1 ]College of Health Sciences and Center for Muscle Biology, University of Kentucky, 900 S Limestone CTW105, Lexington, KY 40536 USA

[2 ]Division of General Internal Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, 750 North Lake Shore Drive, 10th Floor, Chicago, 60611 USA

[3 ]Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL USA

[4 ]Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL USA

[5 ]National Institute on Aging, Baltimore, MD USA

[6 ]Department of Health Research & Policy, Stanford University, Stanford, CA USA

[7 ]Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL USA

[8 ]Jesse Brown Veterans Affairs Medical Center, Chicago, IL USA

[9 ]Department of Family Medicine and Public Health, University of California at San Diego, La Jolla, CA USA

[10 ]Department of Aging and Geriatric Research, University of Florida Institute on Aging, Gainesville, FL USA

Author information

Sarah H. White http://orcid.org/0000-0002-1449-8837

Article

Publisher ID: 1030

DOI: 10.1186/s12967-016-1030-6

PMC ID: 5043620

PubMed ID: 27687713

SO-VID: bcd2518e-323c-4193-b9f0-f0e3035d4e49

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 25 May 2016

Date accepted : 6 September 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: R01HL088589

Award ID: R01HL083064

Award ID: R01HL089619

Award ID: R01HL107510

Award ID: R01HL109244

Award ID: R01AR60701-S1

Award Recipient : Mary M. McDermott Charlotte A. Peterson

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ScienceOpen disciplines: Medicine

Keywords: mitochondria,mitophagy,fiber type,calf muscle,peripheral artery disease

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ScienceOpen disciplines: Medicine

Keywords: mitochondria, mitophagy, fiber type, calf muscle, peripheral artery disease

Walking performance is positively correlated to calf muscle fiber size in peripheral artery disease subjects, but fibers show aberrant mitophagy: an observational study

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Most cited references 46

Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability.

Peripheral arterial disease detection, awareness, and treatment in primary care.

Lower extremity function and subsequent disability: consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery.

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