“Aging is characterized by a progressive decline in physiological function, which is controlled by a complex interaction between environmental and genetic factors. While understanding the biological mechanisms of aging that result from these interactions is an area of intensive investigation, building evidence suggests that alterations in mitochondrial function plays a central role in coordinating the aging process. Mitochondrial bioenergetics of skeletal muscle decline with age, and this decrement may pre-dispose to certain age-related diseases. However, the mitochondrial biology of aging theory extends beyond that of altered intrinsic efficiencies in energy production to include a control over inflammatory responses, proteostasis, oxidative balance, stem cell function and initiation of adaptive stress responses. Coordination of such a complex array of cellular processes requires diverse mitochondrial initiated pathways of intra- and extra-cellular communication.
Mitochondrial-derived peptides (MDP), or mitokines, appear to form a critical retrograde communication pathway between the mitochondria and the wider cell, and may have an endocrine cytoprotective role…
MOTS-c, an MDP with its sequence located within the coding region for mitochondrial 12S rRNA gene, has recently been shown to be induced by metabolic perturbation and translocate to the nucleus where it is involved in regulating nuclear gene expression, including those with antioxidant response elements (ARE) to protect against metabolic stress. A stress mediated mitonuclear communication role of MOTS-c may partly explain why exogenous MOTS-c is capable of preventing diet, aging and menopause associated metabolic discourse and insulin resistance, but has limited impact on the resting metabolism of healthy young mice.”
“Insulin sensitive tissues, such as skeletal muscle and fat, appear to be key target sites of MOTS-c, and levels of MOTS-c in skeletal muscle and plasma of aged mice are reduced. This has led to speculation that MOTS-c is an age related mitokine, however whether human plasma and muscle MOTS-c levels are influenced by healthy aging is unclear. Therefore, we investigated plasma and vastus lateralis muscle MOTS-c levels in human males.” (1)
MOTS-c is a Regulator of Physical Decline and Muscle Homeostasis.
“Systemic MOTS-c treatment in mice significantly enhanced the performance on a treadmill of all age groups (~2-fold). MOTS-c regulated (i) nuclear genes, including those related to metabolism and protein homeostasis, (ii) glucose and amino acid metabolism in skeletal muscle, and (iii) myoblast adaptation to metabolic stress.
Notably, a statistical enrichment analysis on our RNA-seq data, from both mouse skeletal muscle and myoblasts, revealed heat shock factor 1 (HSF1) as a putative transcriptional factor that could regulate gene expression upon MOTS-c treatment. Indeed, siRNA-mediated HSF1 knockdown reversed MOTS-c-dependent stress resistance against glucose restriction/serum deprivation.
Ultimately, late-life initiated intermittent MOTS-c treatment (23.5 months; 3x/week) improved overall physical capacity and trended towards increasing lifespan. Our data indicate that aging is regulated by genes that are encoded not only in the nuclear genome, but also in the mitochondrial genome.
“Our study shows that exercise induces mtDNA-encoded MOTS-c expression in humans. MOTS-c treatment significantly (i) improved physical performance in young, middle-aged, and old mice, (ii) regulated skeletal muscle metabolism and gene expression, and (iii) enhanced adaptation to metabolic stress in C2C12 cells in a HSF1-dependent manner. Thus, it is plausible that the physiological role of exercise-induced MOTS-c is to promote adaptive responses to exercise-related stress conditions (e.g. metabolic imbalance and heat shock) in the skeletal muscle and maintain cellular homeostasis.
Mitochondria are strongly implicated in aging at multiple levels. Here, we present evidence that the mitochondrial genome encodes for instructions to maintain physical capacity (i.e. performance and metabolism) during aging and thereby increase healthspan. MOTS-c treatment initiated in late-life, proximal to the age at which the lifespan curve rapidly descends for C57BL/6N mice, significantly delayed the onset of age-related physical disabilities, suggesting “compression of morbidity” in later life. Interestingly, an exceptionally long-lived Japanese population harbors a mitochondrial DNA (mtDNA) SNP (m.1382A>C) that yields a functional variant of MOTS-c…
Our study shows that exogenously treated MOTS-c enters the nucleus and regulates nuclear gene expression, including those involved in heat shock response and metabolism. Thus, age-related gene networks are comprised of integrated factors encoded by both genomes, which entails a bi-genomic basis for the evolution of aging. Although the detailed molecular mechanism(s) underlying the functions of MOTS-c is an active field of research, we provide a “proof-of-principle” study that realizes the mitochondrial genome as a source for instructions that can regulate physical capacity and healthy aging.” (2)
Age-Related Increases in Muscle MOTS-c Levels are Associated with Fast-to-Slow Muscle Fiber Shift.
“Plasma MOTS-c levels are reduced with aging while muscle levels are increased:
Plasma MOTS-c levels were measured in young (18-30 y), middle-aged (45-55 y) and older (70-81 y) males that were free from any overt disease following an overnight fast. Characteristics of participants are shown in, while all age groups had similar HOMA-IR, plasma LDL and HDL, the older-aged groups had higher fat mass and lower lean mass, and the middle-aged group high plasma triglycerides. Consistent with murine data, both the middle and older groups had lower circulating MOTS-c (by 11 and 21%, respectively) than the young group. Since exogenous MOTS-c treatment of aged or high fat diet challenged mice improves insulin sensitivity and alters body composition we correlated plasma MOTS-c levels with HOMA-IR, and relative fat and lean mass. A weak association was observed with relative lean mass, but not fat mass or HOMA-IR. To determine if differences between the groups could be explained by differences in clinical blood parameter or body composition, ANCOVA analysis was undertaken with % fat, % lean mass, HOMA-IR and plasma triglycerides as covariates (both independently and combined. With these covariates included the main effect for age on plasma MOTS-c remained significant indicating that this is likely an age-dependent effect.
“In addition to loss of muscle mass, aging is associated with a fast-to-slow fiber type shift. Therefore, we determined whether markers of slow (myosin heavy chain type 7, MYH7) and fast (myosin heavy chain type 2, MYH2) type fibers associate with muscle MOTS-c levels. Consistent with the hypothesis that a change in fiber type may account for the increase in muscle MOTS-c levels observed with aging, MYH7 mRNA showed a positive association with muscle MOTS-c levels while MYH2 mRNA was negatively associated. Furthermore, MOTS-c expression was higher in mouse soleus muscle which has a higher proportion of slow type fibers than EDL, gastrocnemius, and tibialis anterior muscles. Higher slow-type fiber content of soleus muscle was confirmed by measuring mRNA levels of Myh7 (type I fiber), Myh2 (type IIa fibers), Myh4 (type IIb fibers) and Myh1 (type IIx fibers) in these muscles. Slow type fibers normally have a greater mitochondrial density, therefore the mitochondrial protein COXIV was determined in muscle samples and used to correct MOTS-c levels for mitochondrial mass. This did not change the increase in muscle MOTS-c expression observed in the middle-aged and older groups compared to the young group, suggesting that the increase in muscle MOTS-c levels was independent of mitochondrial protein levels.” (1)
Endothelial Dysfunction Caused by Lack of MOTS-C.
“Lower circulating endogenous MOTS-c levels in human subjects are associated with impaired coronary endothelial function. In rodents, MOTS-c improves endothelial function in vitro. Thus, MOTS-c represents a novel potential therapeutic target in patients with ED… Although MOTS-c did not have direct vasoactive effects, pretreating aortic rings from rats or RAS mice with MOTS-c improved vessel responsiveness to ACh compared with vessels without MOTS-c treatment… They were divided into two groups based on coronary blood flow response to intracoronary acetylcholine (ACh) as normal endothelial function (≥ 50% increase from baseline) or ED.” (4)
MOTS-c Improved Cardiovascular Disease:
“Mitochondria are complex organelles, playing important roles in cellular energy production, metabolism, and cellular signaling. In the past, we believed that their biogenesis, maintenance, and function depended mainly on the nucleus. Whereas, it has been found that some mitochondria carry their own genomes, and translate a limited number of well characterized proteins, which may even affect the expression of nuclear genes in turn. Mitochondrial genomes, which contain 2 rRNAs, 22 tRNAs and 13 polypeptide subunits of the electron transport chain (ETC) complexes (except Complex Ⅱ), produce proteins involved in oxidative phosphorylation. In recent years, researchers have found that rRNA locus containe small open reading frames (ORFs) that can be transcribed and translated into short peptides with biological activity. These peptides encoded by mitochondrial DNA are released into or out of cells via autocrine or paracrine means, and bind to specific receptors to exert biological effects. Here, we will introduce the roles of these short peptides in detail.” (4)
“The second mtORF-encoded peptide is named as MOTS-c. MOTS-c is a 16 amino acid peptide encoded by mitochondrial 12S rRNA gene and can activate AMP-activated protein kinase (AMPK), which is a regulator that can improve energy metabolism. MOTS-c can prevent insulin resistance and diet-mediated obesity, and ameliorate diabetes and other similar disorders. MOTS-c stimulates glucose uptake, increases glucose utilization, oxidizes fatty acids and inhibits oxidative respiration. In addition to energy metabolism, MOTS-c can protect against coronary endothelial dysfunction by the reduction of the release of pro-inflammatory cytokines and adhesion molecules, which results from the inhibition of NF-κB. Interestingly, MOTS-c has also been identified as a gene expression regulator in the nucleus, leading to retrograde signaling via its interaction with transcription factors. When the cells are under metabolic stressors, MOTS-c can translocate into nucleus binding with nuclei DNA and interacting with ARE-regulating transcription factors to increase cell resistance. This function may hold key implications for organismal aging and age-related diseases by promoting cellular homeostasis in response to metabolic stress, and MOTS-c polymorphism has been found to be associated with human longevity.” (4)
“In human body, we observed a significantly decline in MDPs (e.g. HN, SHLP2, and mots-c) levels of plasma with age, suggesting a correlation between the loss of MDPs and the deteriorating biological processes associated with aging and age-related diseases. The mechanisms of age-related diseases are often oxidative stress and mitochondrial dysfunction.” (4)
(1) D’Souza, Randall F., et al. “Increased Expression of the Mitochondrial Derived Peptide, MOTS-c, in Skeletal Muscle of Healthy Aging Men Is Associated with Myofiber Composition.” Aging (Albany NY), vol. 12, no. 6, 17 Mar. 2020, pp. 5244–5258, www.ncbi.nlm.nih.gov/pmc/articles/PMC7138593/, 10.18632/aging.102944.
(2) Lee, Changhan, et al. “The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance.” Cell Metabolism, vol. 21, no. 3, Mar. 2015, pp. 443–454, www.cell.com/article/S1550-4131(15)00061-3/abs, 10.1016/j.cmet.2015.02.009.
(3) Qin, Qing, et al. “Downregulation of Circulating MOTS-c Levels in Patients with Coronary Endothelial Dysfunction.” International Journal of Cardiology, vol. 254, 1 Mar. 2018, pp. 23–27, pubmed.ncbi.nlm.nih.gov/29242099/, 10.1016/j.ijcard.2017.12.001.
(4) Yang, Yingxi, et al. “The Role of Mitochondria-Derived Peptides in Cardiovascular Disease: Recent Updates.” Biomedicine & Pharmacotherapy, vol. 117, 1 Sept. 2019, p. 109075, www.sciencedirect.com/science/article/pii/S0753332219315781, 10.1016/j.biopha.2019.109075.
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