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

## TL;DR

This study shows that severe leg dysfunction in advanced PAD patients is linked to damage at the neuromuscular junction in calf muscles.

## Contribution

The study reveals novel evidence of neuromuscular junction deterioration in PAD patients, suggesting a new therapeutic target.

## Key findings

- PAD patients show more denervated nAChR clusters and fewer nerve terminal occupancies compared to controls.
- nAChR clusters in PAD patients are larger, more fragmented, and less organized than in controls.
- Fragmented nAChR clusters in PAD patients may impair neuromuscular transmission and leg function.

## Abstract

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.

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.

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 μm2, the area per fragment was 195.9 ± 9.2 versus 107.1 ± 3.1 μm2, 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).

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.

In severe peripheral artery disease (PAD), the neuromuscular junction (NMJ) is damaged, with deterioration of motor nerve terminals and fragmentation of the nicotinic acetylcholine receptor clusters. This likely contributes to the severe leg dysfunction of patients with advanced PAD. Targeting damaged NMJs could offer a novel approach to improving skeletal muscle and leg function in PAD patients.