Transcriptomic and Proteomic of Gastrocnemius Muscle in Peripheral Artery Disease

Luigi Ferrucci, Julián Candia, Ceereena Ubaida-Mohien, Alexey Lyashkov, Nirad Banskota, Christiaan Leeuwenburgh, Stephanie Wohlgemuth, Jack M. Guralnik, Mary Kaileh, Dongxue Zhang, Robert Sufit, Supriyo De, Myriam Gorospe, Rachel Munk, Charlotte A. Peterson, Mary M. McDermott

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Background: Few effective therapies exist to improve lower extremity muscle pathology and mobility loss due to peripheral artery disease (PAD), in part because mechanisms associated with functional impairment remain unclear. Methods: To better understand mechanisms of muscle impairment in PAD, we performed in-depth transcriptomic and proteomic analyses on gastrocnemius muscle biopsies from 31 PAD participants (mean age, 69.9 years) and 29 age- and sex-matched non-PAD controls (mean age, 70.0 years) free of diabetes or limb-threatening ischemia. Results: Transcriptomic and proteomic analyses suggested activation of hypoxia-compensatory mechanisms in PAD muscle, including inflammation, fibrosis, apoptosis, angiogenesis, unfolded protein response, and nerve and muscle repair. Stoichiometric proportions of mitochondrial respiratory proteins were aberrant in PAD compared to non-PAD, suggesting that respiratory proteins not in complete functional units are not removed by mitophagy, likely contributing to abnormal mitochondrial activity. Supporting this hypothesis, greater mitochondrial respiratory protein abundance was significantly associated with greater complex II and complex IV respiratory activity in non-PAD but not in PAD. Rate-limiting glycolytic enzymes, such as hexokinase and pyruvate kinase, were less abundant in muscle of people with PAD compared with non-PAD participants, suggesting diminished glucose metabolism. Conclusions: In PAD muscle, hypoxia induces accumulation of mitochondria respiratory proteins, reduced activity of rate-limiting glycolytic enzymes, and an enhanced integrated stress response that modulates protein translation. These mechanisms may serve as targets for disease modification.

Original languageEnglish
Pages (from-to)1428-1443
Number of pages16
JournalCirculation Research
Volume132
Issue number11
DOIs
StatePublished - May 26 2023

Bibliographical note

Publisher Copyright:
© 2023 Lippincott Williams and Wilkins. All rights reserved.

Keywords

  • biomarkers
  • mitochondria
  • mitophagy
  • proteomics
  • unfolded protein response

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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