# Gastrocnemius Myofiber Type and Mitochondrial Alterations Associated With Peripheral Artery Disease Severity

## TL;DR

This study explores how muscle fiber types and mitochondrial changes in the gastrocnemius muscle relate to the severity of peripheral artery disease.

## Contribution

The study identifies a potential compensatory mechanism involving type 1 myofibers in response to PAD severity.

## Key findings

- Oxidative type 1 myofiber abundance negatively correlates with PAD severity as measured by ABI.
- IMFM- regions in type 1 myofibers may indicate a transition from type 2 to type 1 myofibers.
- Sarcomere disruption in IMFM- regions was confirmed via electron microscopy.

## Abstract

The extent of walking impairment varies among individuals with peripheral artery disease (PAD), which may reflect differences in the adaptability of lower extremity muscles to ischemia-reperfusion injury characteristic of the disease. Analyses of gastrocnemius muscle biopsies from 113 individuals with PAD [mean ankle-brachial index (ABI) = 0.65 ± 0.13, 38 (33.6%) women, 76 (67.2%) Black] showed a wide range of myofiber type distributions (9.6%-82.6% type 1 myofibers). The abundance of oxidative type 1 myofibers negatively correlated with ABI (r = −0.22, P = 0.02), a measure of PAD severity. The abundance of type 1 myofibers also negatively correlated to 2a/x myofiber abundance (r = −0.76, P < 0.001). Eighty % of participants had NCAM+ myofibers, a potential indicator of myofiber denervation. Overall, 3.2% of total myofibers were NCAM+. Of 113 muscle biopsies, 86 (76.1%) contained type 1 myofibers with regions lacking intermyofibrillar mitochondria (IMFM-), which may represent formation of target myofibers. In type 1 myofiber IMFM- areas, 77.8% contained 2x myosin heavy chain and/or the autophagy marker LC3. Electron microscopy within one muscle with IMFM- myofibers confirmed sarcomere disruption in IMFM- regions. These analyses support the possibility of type 2 myofibers transitioning to type 1 in PAD and suggest IMFM- target fibers may represent visualization of this process for the first time. Because type 1 myofibers are more resistant to oxidative damage, results suggest the possibility that a higher proportion of type 1 myofibers in PAD with increasing disease severity may be a compensatory mechanism to maintain muscle.