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Racial Background Alters the Metabolomic Profile of Limb Muscle from Patients with Chronic Limb Threatening Ischemia
Nancy C Edwards
1, Zoë S Terwilliger
2, FeiFei Li
2, Dean J Yamaguchi
3, Thomas D Green
2, Matthew P Goldman
1, Kevin Z Chang
1, Ashlee E Stutsrim
1, Gabriela Velazquez-Ramirez
1, Joseph M McClung
2 1Atrium Health Wake Forest Baptist, Winston Salem, NC;
2Wake Forest University School of Medicine, Winston Salem, NC;
3Ochsner Health, New Orleans, LA
Background: Chronic Limb threatening ischemia (CLTI) represents the end stage of peripheral artery disease. CLTI patients suffer high morbidity and mortality rates, which is compounded by our lack of understanding of the unique biological characteristics of these patients' tissues. This creates difficulties aligning work in the basic sciences with procedural innovation and clinical care. Cellular bioenergetic changes represent a biologic arm of CLTI with the potential to influence each of the other profile defining characteristics. The goal of this study was to compare the metabolomic profiles of lateral gastrocnemius muscles derived from healthy adult volunteers (HA) and CLTI patients from different racial backgrounds (black and white).
Methods: We collected muscle tissue from 23 HA controls (n=14 white, n=9 black) and 22 CLTI patients (n=22 white, n=10 black) and identified approximately 1114 biochemicals via global metabolomic profiling using Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS).
Results: Significant alterations in metabolites related to pain, inflammation, energy metabolism, oxidative stress, sphingolipid, and tissue remodeling were identified in the CLTI tissues. Of particular interest was the identification of “lipid super-pathways.” Fatty Acid (FA) synthesis and metabolism categories were significantly altered in CLTI tissues. Analysis of sub-pathway species revealed substantial increases in CLTI FA species. Short-Long Chain Saturated acylcarnitine species were largely decreased (8/17 significantly decreased, 1/17 significantly increased, 7/17 were unchanged; p<0.05) in CLTI tissues. Mono-unsaturated targets were increased in CLTI tissues (5/10 species increased; p<0.05). The largest biochemical change of the pathway was the Polyunsaturated C22:2 species, which increased almost 8-fold. Specific regulators of fatty acid transport (deoxycarnitine and carnitine) were decreased in CLTI tissues. Elevations in the monounsaturated, polyunsaturated, and dicarboxylate acylcarnitine species in the presence of reductions in carnitine and deoxycarnitine signal disruptions in FA oxidation. Further breakdown of the tissue metabolomics revealed a distinct pattern by patient race. In CLTI patient tissues, white patients demonstrated an increase in 6/32 FA metabolites compared with HA (p<0.05). In stark contrast, black CLTI patient tissues increased 23/32 FA species compared with HA (p<0.05). The specific and uniform increase in Long-Chain FA in this population is unique and concerning when coupled with our previously published data demonstrating black patient limb muscle mitochondrial functional deficits compared to white CLTI counterparts. No differences were observed between black and white HA tissue FA.
Discussion: Limb muscle metabolome of CLTI patients demonstrates a unique profile that is differentially altered by race. In fact, these characteristics are features of the most common fatty acid oxidation clinical diseases, which result in cardio- and skeletal myopathies, hypoglycemia, and recurrent rhabdomyolysis. These results guide our understanding of the biochemical and biologic processes that underlie the CLTI pathophysiology which can aid in developing effective therapies that drive tissue outcomes.
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