Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans

Abstract

Mitochondrial derived peptides (MDPs) humanin (HN) and mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) are involved in cell survival, suppression of apoptosis and metabolism. Circulating levels of MDPs are altered in chronic diseases such as diabetes type 2 and chronic kidney disease. Whether acute resistance (RE) or endurance (EE) exercise modulates circulating levels of HN and MOTS-c in humans is unknown. Following familiarization, subjects were randomized to EE (n=10, 45 min cycling at 70% of estimated VO2max), RE (n=10, 4 sets x 7RM, leg press and knee extension), or control (CON, n=10). Skeletal muscle biopsies and blood samples were collected before and at 30 minutes and 3 hours following exercise. Plasma concentration of HN and MOTS-c, skeletal muscle MOTS-c as well as gene expression of exercise related genes were analyzed. Acute EE and RE promoted changes in skeletal muscle gene expression typically seen in response to each exercise modality (c-Myc, 45S pre-rRNA, PGC-1α-total and PGC-1α-ex1b). At rest, circulating levels of HN were positively correlated to MOTS-c levels and age. Plasma levels of MDPs were not correlated to fitness outcomes (VO2max, leg strength or muscle mitochondrial (mt) DNA copy number). Circulating levels of HN were significantly elevated by acute EE but not RE. MOTS-C levels showed a trend to increase after EE. These results indicate that plasma MDP levels are not related to fitness status but that acute EE increases circulating levels of MDPs, in particular HN.

MOTS ‐c increases in skeletal muscle following long‐term physical activity and improves acute exercise performance after a single dose

“…Additionally, acute exercise performance improved 12%–15% after a single exogenous dose of MOTS‐c. Taken together, these findings suggest that skeletal muscle is an important reservoir for MOTS‐c that can expand with chronic physical activity and, presumably, impact performance through its systemic release during acute exercise (Reynolds et al, 2021 ; von Walden et al, 2021 ).…”

“…MOTS‐c is a mitochondrial‐encoded peptide that improves age‐related skeletal muscle insulin resistance and enhances adaptation to metabolic stress (Kim et al, 2018 , 2019 ; Reynolds et al, 2021 ). Its potential as an important regulator of systemic metabolism was highlighted in a series of studies examining changes in circulating MOTS‐c following high‐intensity exercise (Reynolds et al, 2021 ; von Walden et al, 2021 ) and by exogenously providing MOTS‐c in rodent models (Reynolds et al, 2021 ; Yuan et al, 2021 ). The goal of this study was to better understand the relationship between MOTS‐c and exercise.…”

“…Although humanin localization was not determined in the present study, MOTS‐c protein was consistently absent in the mitochondrial fraction (Figure 6 ), suggesting that MOTS‐c is not limited by the boundaries of the mitochondria to accumulate within the muscle fiber. Indeed, if this accumulation hypothesis is correct, and both MOTS‐c and humanin proteins are not subjected to turnover as quickly as, for example, OXPHOS proteins, then the systemic influence on metabolism by MOTS‐c and humanin would theoretically persist during periods of physical inactivity (e.g., detraining), although it appears that MOTS‐c release from skeletal muscle is, at least, exercise‐dependent (Reynolds et al, 2021 ; von Walden et al, 2021 ). The mechanism of MOTS‐c release into the circulation from skeletal muscle, however, is currently unknown.…”

“…MOTS‐c is abundantly expressed in skeletal muscle (D'Souza et al, 2020 ; Lee et al, 2015 ) and functions, in part, to increase glucose metabolism by enhancing insulin sensitivity, energy expenditure, and heat production (Lee et al, 2015 ). Circulating MOTS‐c decreases with fasting (Lee et al, 2015 ) and increases during short, high‐intensity exercise (Reynolds et al, 2021 ; von Walden et al, 2021 ). In cultured conditions of metabolic stress (i.e., glucose restriction/serum deprivation, oxidative stress), MOTS‐c translocates into the nucleus to influence gene expression in an AMPK‐dependent manner (Kim et al, 2018 ).…”

Extracellular vesicles and high-density lipoproteins: Exercise and estrogen-responsive small RNA carriers

“…For example, the mitochondrial peptide humanin, which originates from the mitochondrial 16S rRNA gene, has been linked to improved insulin action (Kuliawat et al, 2013). It was recently shown in humans that acute endurance exercise stimulates circulating levels of mitochondrial peptides (von Walden et al, 2021). We speculate that the observed changes in mitochondrial rDRs may reflect the response of muscle tissue to exercise, but the potential role of rDRs in coordinating metabolism remains to be uncovered.…”