Neuromuscular Junction Damage in the Calf Muscles of Patients With Advanced Peripheral Artery Disease

Overview

Journal Neuropathol Appl Neurobiol

Specialty Neurology

Date 2025 Feb 24

PMID 39989162

Authors

Huiyin Tu

Ali H Hakim

Julian K Kim

Zhen Zhu

Yuqian Tian

Iraklis I Pipinos

Yu-Long Li

Affiliations

Soon will be listed here.

Abstract

Aims: Peripheral artery disease (PAD) reduces blood flow to the legs and causes severe muscle and leg dysfunction for PAD patients. Skeletal muscle contractile function is dependent on the health of the muscle itself and that of the neuromuscular junction (NMJ) on the muscle membrane.

Methods: To determine whether the NMJ, including the motor nerve terminals and nicotinic acetylcholine receptors (nAChR), is damaged in PAD, gastrocnemius muscles were collected from 3 controls and 13 PAD patients to capture images from 331 control NMJs and 512 PAD NMJs.

Results: For the motor nerve terminals, there were more denervated nAChR clusters and fewer nerve terminal occupancies in NMJs in PAD patients, compared with controls. For the nAChR clusters in the NMJs, the area per nAChR cluster was 369.3 ± 6.7 versus 225.2 ± 5.3 μm, the area per fragment was 195.9 ± 9.2 versus 107.1 ± 3.1 μm, the number of fragments per nAChR cluster was 2.3 ± 0.1 versus 3.2 ± 0.1, the nAChR cluster area per endplate area was 75.7 ± 1.6 versus 55.7 ± 1.1%, total distance of fragments per nAChR cluster was 4.6 ± 0.4 versus 8.8 ± 0.8 μm, and the fragmented nAChR clusters were 7.6% versus 21.6% of total nAChR clusters in controls versus PAD patients, respectively (p < 0.05 in all parameters).

Conclusions: Our data demonstrate deterioration of the motor nerve terminals and nAChR clusters, which may compromise neuromuscular transmission, and contribute to the severe leg dysfunction observed in patients with PAD.

References

Aday A, Matsushita K . Epidemiology of Peripheral Artery Disease and Polyvascular Disease. Circ Res. 2021; 128(12):1818-1832. PMC: 8202714. DOI: 10.1161/CIRCRESAHA.121.318535. View

Clyne C, Weller R, Bradley W, Silber D, ODonnell Jr T, CALLOW A . Ultrastructural and capillary adaptation of gastrocnemius muscle to occlusive peripheral vascular disease. Surgery. 1982; 92(2):434-40. View

Schieber M, Hasenkamp R, Pipinos I, Johanning J, Stergiou N, DeSpiegelaere H . Muscle strength and control characteristics are altered by peripheral artery disease. J Vasc Surg. 2017; 66(1):178-186.e12. PMC: 5484068. DOI: 10.1016/j.jvs.2017.01.051. View

Bonaca M, Gutierrez J, Creager M, Scirica B, Olin J, Murphy S . Acute Limb Ischemia and Outcomes With Vorapaxar in Patients With Peripheral Artery Disease: Results From the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial.... Circulation. 2016; 133(10):997-1005. DOI: 10.1161/CIRCULATIONAHA.115.019355. View

Fagerlund M, Eriksson L . Current concepts in neuromuscular transmission. Br J Anaesth. 2009; 103(1):108-14. DOI: 10.1093/bja/aep150. View

Li L, Xiong W, Mei L . Neuromuscular Junction Formation, Aging, and Disorders. Annu Rev Physiol. 2017; 80:159-188. DOI: 10.1146/annurev-physiol-022516-034255. View

Tu H, Qian J, Zhang D, Barksdale A, Wadman M, Pipinos I . Different responses of skeletal muscles to femoral artery ligation-induced ischemia identified in BABL/c and C57BL/6 mice. Front Physiol. 2022; 13:1014744. PMC: 9523359. DOI: 10.3389/fphys.2022.1014744. View

Rudolf R, Deschenes M, Sandri M . Neuromuscular junction degeneration in muscle wasting. Curr Opin Clin Nutr Metab Care. 2016; 19(3):177-81. PMC: 4946244. DOI: 10.1097/MCO.0000000000000267. View

Tu H, Zhang D, Corrick R, Muelleman R, Wadman M, Li Y . Morphological Regeneration and Functional Recovery of Neuromuscular Junctions after Tourniquet-Induced Injuries in Mouse Hindlimb. Front Physiol. 2017; 8:207. PMC: 5382216. DOI: 10.3389/fphys.2017.00207. View

10.

Pipinos I, Judge A, Selsby J, Zhu Z, Swanson S, Nella A . The myopathy of peripheral arterial occlusive disease: Part 2. Oxidative stress, neuropathy, and shift in muscle fiber type. Vasc Endovascular Surg. 2008; 42(2):101-12. DOI: 10.1177/1538574408315995. View

11.

Jones R, Harrison C, Eaton S, Hurtado M, Graham L, Alkhammash L . Cellular and Molecular Anatomy of the Human Neuromuscular Junction. Cell Rep. 2017; 21(9):2348-2356. PMC: 5723673. DOI: 10.1016/j.celrep.2017.11.008. View

12.

Tu H, Zhang D, Wadman M, Li Y . Dexamethasone ameliorates recovery process of neuromuscular junctions after tourniquet-induced ischemia-reperfusion injuries in mouse hindlimb. Eur J Pharmacol. 2020; 883:173364. DOI: 10.1016/j.ejphar.2020.173364. View

13.

Jones W, Baumgartner I, Hiatt W, Heizer G, Conte M, White C . Ticagrelor Compared With Clopidogrel in Patients With Prior Lower Extremity Revascularization for Peripheral Artery Disease. Circulation. 2016; 135(3):241-250. DOI: 10.1161/CIRCULATIONAHA.116.025880. View

14.

Chervu A, Moore W, Homsher E, Quinones-Baldrich W . Differential recovery of skeletal muscle and peripheral nerve function after ischemia and reperfusion. J Surg Res. 1989; 47(1):12-9. DOI: 10.1016/0022-4804(89)90041-3. View

15.

Zhang D, Wang D, Pipinos I, Muelleman R, Li Y . Dexamethasone promotes long-term functional recovery of neuromuscular junction in a murine model of tourniquet-induced ischaemia-reperfusion. Acta Physiol (Oxf). 2016; 219(2):453-464. DOI: 10.1111/apha.12737. View

16.

Carnio S, LoVerso F, Baraibar M, Longa E, Khan M, Maffei M . Autophagy impairment in muscle induces neuromuscular junction degeneration and precocious aging. Cell Rep. 2014; 8(5):1509-21. PMC: 4534571. DOI: 10.1016/j.celrep.2014.07.061. View

17.

McDermott M, Guralnik J, Ferrucci L, Tian L, Liu K, Liao Y . Asymptomatic peripheral arterial disease is associated with more adverse lower extremity characteristics than intermittent claudication. Circulation. 2008; 117(19):2484-91. PMC: 5077147. DOI: 10.1161/CIRCULATIONAHA.107.736108. View

18.

McDermott M . Lower extremity manifestations of peripheral artery disease: the pathophysiologic and functional implications of leg ischemia. Circ Res. 2015; 116(9):1540-50. PMC: 4410164. DOI: 10.1161/CIRCRESAHA.114.303517. View

19.

McDermott M, Sufit R, Nishida T, Guralnik J, Ferrucci L, Tian L . Lower extremity nerve function in patients with lower extremity ischemia. Arch Intern Med. 2006; 166(18):1986-92. PMC: 2645651. DOI: 10.1001/archinte.166.18.1986. View

20.

Uccioli L, Meloni M, Izzo V, Giurato L, Merolla S, Gandini R . Critical limb ischemia: current challenges and future prospects. Vasc Health Risk Manag. 2018; 14:63-74. PMC: 5927064. DOI: 10.2147/VHRM.S125065. View