Abstract

Although mitochondrial dysfunction has been implicated in aging, physical function decline, and several age-related diseases, an accessible and affordable measure of mitochondrial health is still lacking. In this study we identified the proteomic signature of muscular mitochondrial oxidative capacity in plasma. In 165 adults, we analyzed the association between concentrations of plasma proteins, measured using the SOMAscan assay, and skeletal muscle maximal oxidative phosphorylation capacity assessed as post-exercise phosphocreatine recovery time constant (τPCr) by phosphorous magnetic resonance spectroscopy. Out of 1301 proteins analyzed, we identified 87 proteins significantly associated with τPCr, adjusting for age, sex, and phosphocreatine depletion. Sixty proteins were positively correlated with better oxidative capacity, while 27 proteins were correlated with poorer capacity. Specific clusters of plasma proteins were enriched in the following pathways: homeostasis of energy metabolism, proteostasis, response to oxidative stress, and inflammation. The generalizability of these findings would benefit from replication in an independent cohort and in longitudinal analyses.

Highlights

  • Mitochondrial oxidative phosphorylation is the major source of energy production for all cellular functions [1]

  • The top 10 proteins most strongly associated with τPCr in the first model were endothelial cell-selective adhesion molecule (ESAM), insulin-like growth factor binding protein 3 (IGFBP-3), contactin 2 (CNTN2), p-selectin, proto-oncogene tyrosine-protein kinase Fyn (FYN), lactoperoxidase (PERL), dermatopontin (DERM), C-X-C motif chemokine ligand 16 (CXCL16), Ras-related C3 botulinum toxin substrate 3 (RAC3), and tyrosine-protein kinase Lyn (LYN) (Table 3, Model 1)

  • Using the 1.3 k SOMAscan assay, we found that 87 proteins were associated with mitochondrial oxidative capacity, as measured by 31P-MRS on the quadriceps muscle

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Summary

Introduction

Mitochondrial oxidative phosphorylation is the major source of energy production for all cellular functions [1]. Consistent with the decline of oxidative capacity with aging, discovery proteomic studies in skeletal muscle from healthy individuals over a wide age-range have shown a substantial decline of mitochondrial proteins with aging, including proteins of electron transport chain complexes (ETC), enzymes of the Krebs cycle as well as structural proteins [10]. In a recent study, aimed to define the proteomic signature of mitochondrial oxidative capacity in skeletal muscle, we identified muscle proteins that were differentially represented in individuals with higher and lower oxidative capacity, measured by phosphorus magnetic resonance spectroscopy (31P-MRS) [11]. Proteins overrepresented in muscle with higher oxidative capacity were enriched for pathways connected with mitochondrial metabolism and translation within mitochondria. We found highly significant enrichment for mRNA processing/alternative splicing pathways, this finding remains unexplained [11]

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