Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition

D’Souza, Randall F.; Woodhead, Jonathan S T; Hedges, Christopher P.; Zeng, Nina; Wan, Junxiang; Kumagai, Hiroshi; Lee, Changhan; Cohen, Pinchas; Cameron‐Smith, David; Mitchell, Cameron J.; Merry, Troy L.

doi:10.18632/aging.102944

Cited by 39 publications

(36 citation statements)

References 49 publications

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“…However, the bioinactive K14Q MOTS-c may increase T2D risk, particularly in the susceptible sedentary group. We propose the concept that some variants of mtDNA evolved to best fit living conditions characterized by highly active lifestyles and limited caloric intake, where K14Q MOTS-c, which might be less effective in fast-to-slow type muscle fiber transition and increase fast type fiber [ 18 ], might present an advantage, but in the twenty-first century, it is a metabolic liability.…”

Section: Discussionmentioning

confidence: 99%

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A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c

Zempo

Kim

Fuku

et al. 2021

Aging

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Type 2 Diabetes (T2D) is an emerging public health problem in Asia. Although ethnic specific mtDNA polymorphisms have been shown to contribute to T2D risk, the functional effects of the mtDNA polymorphisms and the therapeutic potential of mitochondrial-derived peptides at the mtDNA polymorphisms are underexplored. Here, we showed an Asian-specific mitochondrial DNA variation m.1382A>C (rs111033358) leads to a K14Q amino acid replacement in MOTS-c, an insulin sensitizing mitochondrial-derived peptide. Meta-analysis of three cohorts (n = 27,527, J-MICC, MEC, and TMM) show that males but not females with the C-allele exhibit a higher prevalence of T2D. In J-MICC, only males with the C-allele in the lowest tertile of physical activity increased their prevalence of T2D, demonstrating a kinesio-genomic interaction. High-fat fed, male mice injected with MOTS-c showed reduced weight and improved glucose tolerance, but not K14Q-MOTS-c treated mice. Like the human data, female mice were unaffected. Mechanistically, K14Q-MOTS-c leads to diminished insulin-sensitization in vitro . Thus, the m.1382A>C polymorphism is associated with susceptibility to T2D in men, possibly interacting with exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c.

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Section: Discussionmentioning

confidence: 99%

“…MOTS-c reduces weight gain and decreases fat accumulation in the liver in high-fat diet-induced obese mice. MOTS-c levels correlate with muscle fiber composition in men [ 18 ], leading some to calling it an “exercise-mimetic peptide” [ 19 ]. MOTS-c also prevents ovariectomy-induced metabolic dysfunction [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c

Zempo

Kim

Fuku

et al. 2021

Aging

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“…On the other hand, we observed a negative correlation between skeletal muscle mtDNA copy number and skeletal muscle MOTS-c levels. Interestingly, during normal healthy aging, when skeletal muscle mitochondrial content is known to decline with advancing age, skeletal muscle MOTS-c levels have been reported to increase (17). The reason for this has been suggested to be a reactive oxygen species (ROS)-dependent response (22).…”

Section: Discussionmentioning

confidence: 99%

“…HN and MOTS-c levels in plasma and skeletal muscle were measured by in-house sandwich enzyme-linked immunosorbent assay (ELISA) (10,16,17). Prior to assay, HN and MOTSc in plasma or skeletal muscle extracts were extracted in 90% acetonitrile and 10% of 1 N HCl.…”

Section: Analysis Of Hn and Mots-c In Plasma And Skeletal Musclementioning

confidence: 99%

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

Walden

Fernandez‐Gonzalo

Norrbom

et al. 2021

Journal of Applied Physiology

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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.

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“…However, several studies have demonstrated that Nrf2 is a central mediator for improvements in mitochondrial function. Nrf2 at least partially mediates exercise-induced mitochondrial biogenesis and improvement in mitochondrial function (Merry & Ristow, 2016; D’Souza et al ., 2020; Islam et al ., 2020). Interestingly, both Nrf2-related redox signaling (Safdar et al ., 2010) and Complex I function decrease with age in skeletal muscle (Kruse et al ., 2016).…”

Section: Discussionmentioning

confidence: 99%

Phytochemical Nrf2 activator attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a preclinical model of musculoskeletal aging

Musci

et al. 2021

Preprint

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Musculoskeletal dysfunction is an age-related syndrome associated with impaired mitochondrial function and proteostasis. However, few interventions have tested targeting two drivers of musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that stimulates transcription of cytoprotective genes and improves mitochondrial function. We hypothesized daily treatment with a Nrf2 activator in Hartley guinea pigs, a model of age-related musculoskeletal dysfunction, attenuates the progression of skeletal muscle mitochondrial dysfunction and impaired proteostasis, preserving musculoskeletal function. We treated 2-month- and 5-month-old male and female Hartley guinea pigs for 3 and 10 months, respectively, with the phytochemical Nrf2 activator PB125 (Nrf2a). Longitudinal assessments of voluntary mobility were measured using Any-Maze™ open-field enclosure monitoring. Cumulative skeletal muscle protein synthesis rates were measured using deuterium oxide over the final 30 days of treatment. Mitochondrial oxygen consumption in permeabilized soleus muscles was measured using ex vivo high resolution respirometry. In both sexes, Nrf2a 1) increased electron transfer system capacity; 2) attenuated the disease/age-related decline in coupled and uncoupled mitochondrial respiration; and 3) attenuated declines in protein synthesis in the myofibrillar, mitochondrial, and cytosolic subfractions of the soleus. These improvements were not associated with statistically significant prolonged maintenance of voluntary mobility in guinea pigs. Collectively, these results demonstrate that treatment with an oral Nrf2 activator contributes to maintenance of skeletal muscle mitochondrial function and proteostasis in a pre-clinical model of musculoskeletal decline. Further investigation is necessary to determine if these improvements are also accompanied by slowed progression of other aspects of musculoskeletal decline.

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Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition

Cited by 39 publications

References 49 publications

A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c

A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c

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

Phytochemical Nrf2 activator attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a preclinical model of musculoskeletal aging

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