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



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.



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.



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.
College of Health Sciences and Center for Muscle Biology, University of Kentucky, 900 S Limestone CTW105, Lexington, KY, 40536, USA.
Sarah H
0000-0002-1449-8837
SH
White
Division of General Internal Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, 750 North Lake Shore Drive, 10th Floor, Chicago, 60611, USA. mdm608@northwestern.edu.|Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. mdm608@northwestern.edu.
Mary M
MM
McDermott
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Robert L
RL
Sufit
College of Health Sciences and Center for Muscle Biology, University of Kentucky, 900 S Limestone CTW105, Lexington, KY, 40536, USA.
Kate
K
Kosmac
College of Health Sciences and Center for Muscle Biology, University of Kentucky, 900 S Limestone CTW105, Lexington, KY, 40536, USA.
Alex W
AW
Bugg
National Institute on Aging, Baltimore, MD, USA.
Marta
M
Gonzalez-Freire
National Institute on Aging, Baltimore, MD, USA.
Luigi
L
Ferrucci
Department of Health Research & Policy, Stanford University, Stanford, CA, USA.
Lu
L
Tian
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Lihui
L
Zhao
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Ying
Y
Gao
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA.
Melina R
MR
Kibbe
Department of Family Medicine and Public Health, University of California at San Diego, La Jolla, CA, USA.
Michael H
MH
Criqui
Department of Aging and Geriatric Research, University of Florida Institute on Aging, Gainesville, FL, USA.
Christiaan
C
Leeuwenburgh
College of Health Sciences and Center for Muscle Biology, University of Kentucky, 900 S Limestone CTW105, Lexington, KY, 40536, USA. cpete4@uky.edu.
Charlotte A
CA
Peterson
D000368:Aged; D002196:Capillaries / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D063306:Mitophagy; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D058729:Peripheral Arterial Disease / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D016138:Walking / Q000502:physiology*
C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D013385:Succinate Dehydrogenase
Calf muscle; Fiber type; Mitochondria; Mitophagy; Peripheral artery disease
Contemp Clin Trials. 2013 Nov;36(2):502-9
24080099
Med Sci Sports Exerc. 2001 Dec;33(12):2016-21
11740293
JAMA. 2001 Oct 3;286(13):1599-606
11585483
Redox Biol. 2014 Jul 19;2:921-8
25180168
Circ Cardiovasc Imaging. 2011 May;4(3):246-52
21436300
Orphanet J Rare Dis. 2007 May 15;2:25
17504518
Injury. 2012 Jun;43(6):670-5
21481870
Circulation. 2000 Mar 7;101(9):1007-12
10704168
J Am Coll Cardiol. 2008 Apr 15;51(15):1482-9
18402904
JAMA. 2004 Jul 28;292(4):453-61
15280343
JAMA. 2001 Sep 19;286(11):1317-24
11560536
Heart Fail Rev. 2013 Sep;18(5):607-22
22948484
J Am Coll Cardiol. 2004 Aug 4;44(3):618-23
15358030
Arch Biochem Biophys. 2007 Jun 15;462(2):245-53
17475204
J Vasc Surg. 2000 Mar;31(3):443-9
10709055
Nature. 2014 Nov 20;515(7527):431-5
25383517
Circulation. 2012 Dec 11;126(24):2890-909
23159553
Vasc Med. 2003 May;8(2):115-26
14518614
Ann Surg. 2015 Mar;261(3):605-10
24670845
JAMA. 2013 Jul 3;310(1):57-65
23821089
J Am Coll Cardiol. 2009 Mar 24;53(12):1056-62
19298919
J Am Coll Cardiol. 2009 Aug 11;54(7):628-35
19660694
Vasc Med. 1996;1(1):65-71
9546918
Glycoconj J. 1993 Apr;10(2):181-8
8400828
J Vasc Surg. 2000 Dec;32(6):1164-71
11107089
J Biomed Biotechnol. 2010;2010:724914
20467471
Angiology. 1993 Jan;44(1):1-10
8424578
JAMA. 2013 Aug 14;310(6):591-608
23842577
J Vasc Surg. 2003 Oct;38(4):827-32
14560237
Contemp Clin Trials. 2012 Nov;33(6):1311-20
23158112
J Gerontol A Biol Sci Med Sci. 2000 Apr;55(4):M221-31
10811152
J Physiol. 2016 Aug 15;594(16):4499-512
26921061
Am J Physiol Cell Physiol. 2012 Feb 15;302(4):C629-41
22031602
J Am Coll Cardiol. 1989 Nov 15;14(6):1464-73
2809005
Vasc Endovascular Surg. 2008 Apr-May;42(2):101-12
18390972
J Anat. 2013 Feb;222(2):223-30
23231035
J Histochem Cytochem. 2015 Apr;63(4):256-69
25575565
J Transl Med. 2013 Sep 25;11:230
24067235
J Am Geriatr Soc. 2011 Jul;59(7):1217-24
21718263
Contemp Clin Trials. 2014 May;38(1):121-9
24721480
Surgery. 1982 Aug;92(2):434-40
7101134
N Engl J Med. 1995 Mar 2;332(9):556-61
7838189
J Am Coll Cardiol. 2007 Sep 4;50(10):974-82
17765125
Free Radic Biol Med. 2006 Jul 15;41(2):262-9
16814106
J Vasc Surg. 2004 Jul;40(1):73-8
15218465
Am J Pathol. 2010 Sep;177(3):1377-87
20616343
Circulation. 1993 Feb;87(2):413-21
8425290
Ann Intern Med. 2002 Jun 18;136(12):873-83
12069561
Vasc Med. 2016 Feb;21(1):12-20
26647446
FASEB J. 2001 Feb;15(2):322-32
11156948
Compr Physiol. 2012 Oct;2(4):2933-3017
23720270
JAMA. 2008 Jul 9;300(2):197-208
18612117