PFKFB3-mediated glycolysis rescues myopathic outcomes in the ischemic limb

Terence E. Ryan, Cameron A. Schmidt, Michael D. Tarpey, Adam J. Amorese, Dean J. Yamaguchi, Emma J. Goldberg, Melissa M.R. Iñigo, Reema Karnekar, Allison O'Rourke, James M. Ervasti, Patricia Brophy, Thomas D. Green, P. Darrell Neufer, Kelsey Fisher-Wellman, Espen E. Spangenburg, Joseph M. McClung

Research output: Contribution to journalArticlepeer-review

Abstract

Compromised muscle mitochondrial metabolism is a hallmark of peripheral arterial disease, especially in patients with the most severe clinical manifestation - critical limb ischemia (CLI). We asked whether inflexibility in metabolism is critical for the development of myopathy in ischemic limb muscles. Using Polg mtDNA mutator (D257A) mice, we reveal remarkable protection from hind limb ischemia (HLI) due to a unique and beneficial adaptive enhancement of glycolytic metabolism and elevated ischemic muscle PFKFB3. Similar to the relationship between mitochondria from CLI and claudicating patient muscles, BALB/c muscle mitochondria are uniquely dysfunctional after HLI onset as compared with the C57BL/6 (BL6) parental strain. AAV-mediated overexpression of PFKFB3 in BALB/c limb muscles improved muscle contractile function and limb blood flow following HLI. Enrichment analysis of RNA sequencing data on muscle from CLI patients revealed a unique deficit in the glucose metabolism Reactome. Muscles from these patients express lower PFKFB3 protein, and their muscle progenitor cells possess decreased glycolytic flux capacity in vitro. Here, we show supplementary glycolytic flux as sufficient to protect against ischemic myopathy in instances where reduced blood flow-related mitochondrial function is compromised preclinically. Additionally, our data reveal reduced glycolytic flux as a common characteristic of the failing CLI patient limb skeletal muscle.

Original languageEnglish (US)
Article numbere139628
JournalJCI Insight
Volume5
Issue number18
DOIs
StatePublished - Aug 2020

Bibliographical note

Funding Information:
This work was supported in part by NIH and DOD grants R01HL125695 (JMM), R01AR066660 (EES), DOD-W81XWH-19-1-0213 (KFW), DK074825 and DK110656 (PDN), and AR049899 (JME). TER was supported by F32HL129632. During the preparation of this manuscript, TER moved to a position within the Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA.

Publisher Copyright:
Copyright: © 2020, Ryan et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

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