Older Adults with Physical Frailty and Sarcopenia Show Increased Levels of Circulating Small Extracellular Vesicles with a Specific Mitochondrial Signature

Abstract

Mitochondrial dysfunction and systemic inflammation are major factors in the development of sarcopenia, but the molecular determinants linking the two mechanisms are only partially understood. The study of extracellular vesicle (EV) trafficking may provide insights into this relationship. Circulating small EVs (sEVs) from serum of 11 older adults with physical frailty and sarcopenia (PF&S) and 10 controls were purified and characterized. Protein levels of three tetraspanins (CD9, CD63, and CD81) and selected mitochondrial markers, including adenosine triphosphate 5A (ATP5A), mitochondrial cytochrome C oxidase subunit I (MTCOI), nicotinamide adenine dinucleotide reduced form (NADH):ubiquinone oxidoreductase subunit B8 (NDUFB8), NADH:ubiquinone oxidoreductase subunit S3 (NDUFS3), succinate dehydrogenase complex iron sulfur subunit B (SDHB), and ubiquinol-cytochrome C reductase core protein 2 (UQCRC2) were quantified by Western immunoblotting. Participants with PF&S showed higher levels of circulating sEVs relative to controls. Protein levels of CD9 and CD63 were lower in the sEV fraction of PF&S older adults, while CD81 was unvaried between groups. In addition, circulating sEVs from PF&S participants had lower amounts of ATP5A, NDUFS3, and SDHB. No signal was detected for MTCOI, NDUFB8, or UQCRC2 in either participant group. Our findings indicate that, in spite of increased sEV secretion, lower amounts of mitochondrial components are discarded through EV in older adults with PF&S. In-depth analysis of EV trafficking might open new venues for biomarker discovery and treatment development for PF&S.

Biomarkers of Physical Frailty and Sarcopenia: Coming up to the Place?

“…Recent findings by our group support the hypothesis of mitochondrial impairment among the underlying pathogenetic mechanisms of sarcopenia [18]. In particular, as a result of failing quality control systems [91,[95][96][97], the release of oxidized cell-free mtDNA and other mitochondrial components within MDVs have been associated with systemic inflammation in older adults with PF&S [7].…”

“…The decline in physical function is, indeed, the most evident change that occurs during sarcopenia, and a cardinal criterion for the identification of PF&S [7][8][9][10]. Physical function refers to a construct encompassing simple single-joint (e.g., handgrip strength) and multi-joint complex movements (e.g., walking speed), and may be assessed through a large array of tests [11,12].…”

“…When exploring the pathways and processes involved in PF&S pathophysiology, several factors, from muscle-specific mitochondrial dysfunction to systemic changes (e.g., inflammation and amino acid dysmetabolism), have been pinpointed [9,10,18]. It is still unclear whether these processes share common roots and how cell-based alterations spread and are detected at the systemic level, contributing to the disabling cascade that characterizes PF&S. Low-grade inflammation and amino acid dysmetabolism have recently been associated with a specific pattern of small extracellular vesicles (sEVs) of mitochondrial origin, namely mitochondrial-derived vesicles (MDVs), which are proposed to function as shuttles that allow crosstalk between biological systems [7]. However, little is known about their complex regulatory network.…”

“…The pathophysiology of PF&S recapitulates all the hallmarks of aging [19][20][21], which makes it a prototypical geroscience condition [22]. In this scenario, multivariate analyses of biomediators, pertaining to different domains, may enable the identification of biomarkers for PF&S that capture its pathophysiological complexity ( Figure 1) [7][8][9][10]23]. The identified pathways may, eventually, be used for drug development.…”

Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities

“…These vesicles transfer information between cells through several categories of cargo-enriched biomolecules (i.e., proteins, lipids, nucleic acids, and sugars), each of them selectively influencing different cellular domains. Picca et al, demonstrated that older adults with physical frailty and sarcopenia show increased levels of circulating small extracellular vesicles with a specific mitochondrial signature [12].…”