PHYSIOLOGICAL CHARACTERIZATION OF A HYPOXIA-RESISTANT SKELETAL MUSCLE

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Adam James Amorese (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Across the human lifespan, ischemia induces or exacerbates numerous skeletal muscle myopathies, leading to a loss of force producing capacity which directly contributes to reduced functional independence and a rise in mortality. Current dogma states tissues most distal to the site of arterial occlusion suffer the greatest ischemic burden and necrotic pathology, suggesting that distal tissue is highly dependent on limb blood flow and O2 availability. However, using a mouse model of femoral artery occlusion, we found that one of the most distal peripheral limb muscles, the flexor digitorum brevis (FDB), retains capacity for normal force production for days, despite the complete cessation of blood flow. In contrast, more proximal muscles (i.e. extensor digitorum longus (EDL) and soleus) that experience the same uniform loss of blood flow and O2 tension exhibit a rapid and dramatic loss of force production. Consistent with the in vivo findings, the same force decline occurs in EDL and soleus muscle during exposure to hypoxia ex vivo (95%N2/5%CO2) compared to EDL and soleus muscles exposed to (95%O2/5%CO2), whereas the FDB muscle retains force production in both conditions. In addition, we find the FDB does not demonstrate signs of sarcolemmal membrane damage during an ischemic or hypoxic insult, while in contrast, the EDL and soleus both exhibit signs of significant membrane damage following exposure. Adenine nucleotide analyses revealed that unlike the EDL or soleus muscles, the FDB was able to maintain the [ATP]/[ADP] ratio during hypoxia, as well as [ATP]/[AMP] ratio and IMP concentration, suggesting the FDB uses unique biological strategies that govern ATP generation and/or ATP utilization during hypoxia. We sought to dissect the contribution of different ATP generating pathways to force production during a hypoxic insult. With inhibition of mitochondrial respiration, we found EDL and soleus muscles exposed to KCN exhibit a rapid loss in force production, while in contrast, the FDB shows minimal loss of force production ([less-than]20%). When glycolysis was inhibited, all three muscles exhibited force loss in hypoxic conditions with almost a complete loss in force production after 90 mins. Additionally, we examined how the regulation of two ATPases, myosin ATPase and SERCA, may be contributing to protection from hypoxia in the FDB. Ultimately, we did not find evidence showing regulation of these ATPases conferring protection from the hypoxic insult. Collectively, the data suggest that the FDB is resistant to ischemic or hypoxic insults in part because of its regulation of ATP-generating pathways, while regulation of ATP-consuming ATPases is not critical to survival.

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Language: English

Date: 2020

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