Muscle forces and power are significantly reduced during walking in patients with peripheral artery disease

Rahman, Hafizur; Anderson, Cody; Pipinos, Iraklis I.; Johanning, Jason M.; Casale, George P.; Dong, Jianghu; DeSpiegelaere, Holly; Hassan, Mahdi; Myers, Sara A.

doi:10.1016/j.jbiomech.2022.111024

Cited by 5 publications

(3 citation statements)

References 37 publications

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“…In recent years, there has been an emergence of information documenting the skeletal muscle pathology in lower limbs in patients with PAD 21,27,28,30,35,58,[98][99][100][101][102][103] ; however, the mechanisms driving lower limb functional impairment and mobility loss remain poorly understood. A few studies have employed wide-ranging omics technologies, such as RNA-sequencing and metabolomics, to uncover novel genes/pathways associated with PAD outcomes, [104][105][106] however these studies utilized blood specimens rather than muscle biopsies obtained from below the atherosclerotic lesion.…”

Section: Discussionmentioning

confidence: 99%

Single-Nuclei RNA-Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease

Pass,

Palzkill,

Tan

et al. 2023

Circulation Research

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Background: Lower extremity peripheral artery disease (PAD) is a growing epidemic with limited effective treatment options. Here, we provide a single-nuclei atlas of PAD limb muscle to facilitate a better understanding of the composition of cells and transcriptional differences that comprise the diseased limb muscle. Methods: We obtained gastrocnemius muscle specimens from 20 patients with PAD and 12 non-PAD controls. Nuclei were isolated and single-nuclei RNA-sequencing was performed. The composition of nuclei was characterized by iterative clustering via principal component analysis, differential expression analysis, and the use of known marker genes. Bioinformatics analysis was performed to determine differences in gene expression between PAD and non-PAD nuclei, as well as subsequent analysis of intercellular signaling networks. Additional histological analyses of muscle specimens accompany the single-nuclei RNA-sequencing atlas. Results: Single-nuclei RNA-sequencing analysis indicated a fiber type shift with patients with PAD having fewer type I (slow/oxidative) and more type II (fast/glycolytic) myonuclei compared with non-PAD, which was confirmed using immunostaining of muscle specimens. Myonuclei from PAD displayed global upregulation of genes involved in stress response, autophagy, hypoxia, and atrophy. Subclustering of myonuclei also identified populations that were unique to PAD muscle characterized by metabolic dysregulation. PAD muscles also displayed unique transcriptional profiles and increased diversity of transcriptomes in muscle stem cells, regenerating myonuclei, and fibro-adipogenic progenitor cells. Analysis of intercellular communication networks revealed fibro-adipogenic progenitors as a major signaling hub in PAD muscle, as well as deficiencies in angiogenic and bone morphogenetic protein signaling which may contribute to poor limb function in PAD. Conclusions: This reference single-nuclei RNA-sequencing atlas provides a comprehensive analysis of the cell composition, transcriptional signature, and intercellular communication pathways that are altered in the PAD condition.

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Section: Discussionmentioning

confidence: 99%

Single-Nuclei RNA-Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease

Pass,

Palzkill,

Tan

et al. 2023

Circulation Research

View full text Add to dashboard Cite

show abstract

“…In recent years there has been an emergence of informaOon documenOng the skeletal muscle pathology in lower limbs in paOents with PAD 21,27, 28,30,35,57,[100][101][102][103][104][105] , however the mechanisms driving lower limb funcOonal impairment and mobility loss remain poorly understood. A few studies have employed wide-ranging 'omics' technologies, such as RNA sequencing and metabolomics, to uncover novel genes/pathways associated with PAD outcomes [106][107][108] , however these studies uOlized blood specimens rather than muscle biopsies obtained from below the atheroscleroOc lesion.…”

Section: Discussionmentioning

confidence: 99%

Single Nuclei RNA Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease

Pass¹,

Palzkill²,

Tan³

et al. 2023

Preprint

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Background: Lower extremity peripheral artery disease (PAD) is a growing epidemic with limited effective treatment options. Herein, we provide a single nuclei atlas of PAD limb muscle to facilitate a better understanding of the composition of cells and transcriptional differences that comprise the diseased limb muscle. Methods: We obtained gastrocnemius muscle specimens from 20 PAD patients and 12 non-PAD controls. Nuclei were isolated and single nuclei RNA sequencing (snRNAseq) was performed. The composition of nuclei was characterized by iterative clustering via principal component analysis, differential expression analysis, and the use of known marker genes. Bioinformatics analysis was performed to determine differences in gene expression between PAD and non-PAD nuclei, as well as subsequent analysis of intercellular signaling networks. Additional histological analyses of muscle specimens accompany the snRNAseq atlas. Results: snRNAseq analysis indicated a fiber type shift with PAD patients having fewer Type I (slow/oxidative) and more Type II (fast/glycolytic) myonuclei compared to non-PAD, which was confirmed using immunostaining of muscle specimens. Myonuclei from PAD displayed global upregulation of genes involved in stress response, autophagy, hypoxia, and atrophy. Subclustering of myonuclei also identified populations that were unique to PAD muscle characterized by metabolic dysregulation. PAD muscles also displayed unique transcriptional profiles and increased diversity of transcriptomes in muscle stem cells, regenerating myonuclei, and fibro-adipogenic progenitor (FAPs) cells. Analysis of intercellular communication networks revealed FAPs as a major signaling hub in PAD muscle, as well as deficiencies in angiogenic and bone morphogenetic protein signaling which may contribute to poor limb function in PAD. Conclusions: This reference snRNAseq atlas provides a comprehensive analysis of the cell composition, transcriptional signature, and intercellular communication pathways that are altered in the PAD condition.

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“…The frequency of normal gait has an upper limit between 4Hz to 6Hz [ 40 ]. According to the Nyquist sampling theorem that suggests that the sampling rate must be at least twice as the highest frequency of the signal [ 41 ], we chose 60Hz as sampling frequency like our previous studies [ 42 , 43 ]. Kinetic data were acquired using one Kistler piezoelectric force platform (Kistler North America, Amherst, NY) sampling at 600Hz.…”

Section: Methodsmentioning

confidence: 99%

Peripheral artery disease affects the function of the legs of claudicating patients in a diffuse manner irrespective of the segment of the arterial tree primarily involved

et al. 2022

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Different levels of arterial occlusive disease (aortoiliac, femoropopliteal, multi-level disease) can produce claudication symptoms in different leg muscle groups (buttocks, thighs, calves) in patients with peripheral artery disease (PAD). We tested the hypothesis that different locations of occlusive disease uniquely affect the muscles of PAD legs and produce distinctive patterns in the way claudicating patients walk. Ninety-seven PAD patients and 35 healthy controls were recruited. PAD patients were categorized to aortoiliac, femoropopliteal and multi-level disease groups using computerized tomographic angiography. Subjects performed walking trials both pain-free and during claudication pain and joint kinematics, kinetics, and spatiotemporal parameters were calculated to evaluate the net contribution of the calf, thigh and buttock muscles. PAD patients with occlusive disease affecting different segments of the arterial tree (aortoiliac, femoropopliteal, multi-level disease) presented with symptoms affecting different muscle groups of the lower extremity (calves, thighs and buttocks alone or in combination). However, no significant biomechanical differences were found between PAD groups during the pain-free conditions with minimal differences between PAD groups in the claudicating state. All statistical differences in the pain-free condition occurred between healthy controls and one or more PAD groups. A discriminant analysis function was able to adequately predict if a subject was a control with over 70% accuracy, but the function was unable to differentiate between PAD groups. In-depth gait analyses of claudicating PAD patients indicate that different locations of arterial disease produce claudication symptoms that affect different muscle groups across the lower extremity but impact the function of the leg muscles in a diffuse manner generating similar walking impairments.

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Muscle forces and power are significantly reduced during walking in patients with peripheral artery disease

Cited by 5 publications

References 37 publications

Single-Nuclei RNA-Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease

Single-Nuclei RNA-Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease

Single Nuclei RNA Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease

Peripheral artery disease affects the function of the legs of claudicating patients in a diffuse manner irrespective of the segment of the arterial tree primarily involved

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