Proteomic signatures of in vivo muscle oxidative capacity in healthy adults

Abstract

Adequate support of energy for biological activities and during fluctuation of energetic demand is crucial for healthy aging; however, mechanisms for energy decline as well as compensatory mechanisms that counteract such decline remain unclear. We conducted a discovery proteomic study of skeletal muscle in 57 healthy adults (22 women and 35 men; aged 23–87 years) to identify proteins overrepresented and underrepresented with better muscle oxidative capacity, a robust measure of in vivo mitochondrial function, independent of age, sex, and physical activity. Muscle oxidative capacity was assessed by 31P magnetic resonance spectroscopy postexercise phosphocreatine (PCr) recovery time (τPCr) in the vastus lateralis muscle, with smaller τPCr values reflecting better oxidative capacity. Of the 4,300 proteins quantified by LC‐MS in muscle biopsies, 253 were significantly overrepresented with better muscle oxidative capacity. Enrichment analysis revealed three major protein clusters: (a) proteins involved in key energetic mitochondrial functions especially complex I of the electron transport chain, tricarboxylic acid (TCA) cycle, fatty acid oxidation, and mitochondrial ABC transporters; (b) spliceosome proteins that regulate mRNA alternative splicing machinery, and (c) proteins involved in translation within mitochondria. Our findings suggest that alternative splicing and mechanisms that modulate mitochondrial protein synthesis are central features of the molecular mechanisms aimed at maintaining mitochondrial function in the face of impairment. Whether these mechanisms are compensatory attempt to counteract the effect of aging on mitochondrial function should be further tested in longitudinal studies.

Unbiased Proteomics, Histochemistry, and Mitochondrial DNA Copy Number Reveal Better Mitochondrial Health in Muscle of High Functioning Octogenarians

“…Such a resilience response is not required in MA because of high mitochondrial function maintenance despite old age (Ubaida- Mohien et al, 2019a). This hypothesis is consistent with previous data showing that after adjusting for age and physical activity, better skeletal muscle oxidative capacity assessed by 31 P-MR spectroscopy is associated with overrepresentation of splicing machinery and pre-RNA processing proteins (Adelnia et al, 2020).…”

A cross-sectional study of functional and metabolic changes during aging through the lifespan in male mice

“…In this context, the nature of the processes (e.g. metabolic, immunologic) and underlying mechanisms causing these compensatory maladaptations are not well understood ( Ferrucci et al, 2020 ; Adelnia et al, 2020 ). All hallmarks of aging exhibit prominent anabolic and catabolic effects ( López-Otín et al, 2013 ).…”

Proteomics and Epidemiological Models of Human Aging

“…More specifically, in the condition of a relative scarcity of energy, biological pathways are activated through alternative splicing that spare energy (i.e., inhibition of protein synthesis) and stimulate the production of energy (mitochondrial biogenesis, glycolysis). This hypothesis was verified by confirming that, after adjusting for potential confounders, splicing proteins were significantly associated with mitochondrial function assessed by P31 Magnetic Resonance Spectroscopy (Adelnia et al, 2020). A more recent approach to proteomics and aging is the development of "proteomic clocks."…”