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

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.

Keywords: denervation; ischemia; mitochondria; myofiber type transition; peripheral artery disease; skeletal muscle.