In peripheral artery disease (PAD), low levels of oxygen in the legs cause a cascade of molecular changes that may contribute to impaired mobility, according to a research team led by NIA scientists. The findings, published in Circulation Research, provide a foundation for future studies exploring therapeutic targets that may improve quality of life for people with PAD.
In PAD, plaques in arteries restrict blood flow and oxygen to the lower extremities, eventually leading to mobility decline. However, exactly how PAD causes skeletal muscle damage and mobility impairment has remained unclear. Partly due to this knowledge gap, very few effective treatments have been identified. To better understand the biological pathway of PAD, the research team in this study studied calf muscle cells from people with and without the disease.
First, the researchers measured the amount of all the different proteins and RNA in the muscle cells. Then, they looked for key differences between the molecular pathways in the muscle cells from people with and without PAD. The muscle cells from people with PAD had changes in RNA and proteins consistent with processes known to occur in oxygen-deprived tissue, including inflammation, controlled cell death, and the growth of new blood vessels. Notably, the scientists found the muscle cells from PAD patients had higher amounts of certain proteins found in the mitochondria. These mitochondrial proteins are involved in creating adenosine triphosphate (ATP), which fuels cells. Despite having more of these proteins, the researchers found that the muscle cells from PAD patients did not create ATP more efficiently.
In healthy cells, different mitochondrial proteins are present in specific ratios because they work together to make ATP. The scientists found that in muscle cells from PAD patients, the mitochondrial proteins were present in the wrong proportions, suggesting that many of the proteins were not present in complete functional units. Their analysis also revealed that the PAD samples had impaired mitophagy, a process in which the cell removes aged and damaged mitochondria. Based on these data, the scientists hypothesize that in the PAD samples, debris from old or abnormal mitochondria is not cleared efficiently, causing a buildup of mitochondrial proteins that cannot be used in energy production.
While the study identified differences between muscle cells from individuals with and without PAD, the authors did not conclude that PAD causes these molecular changes. Rather, this study provides a foundation for future research exploring whether any of the pathways and molecules disrupted in PAD may be potential therapeutic targets. As an example, the authors suggest drugs or behavioral interventions that increase the clearance of damaged mitochondria may hold promise for improving mobility in people with PAD.
Reference: Ferrucci L, et al. Transcriptomic and proteomic of gastrocnemius muscle in peripheral artery disease. Circulation Research. 2023. Epub May 8. doi: 10.1161/CIRCRESAHA.122.322325.
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