Lipids and insulin regulate mitochondrial‐derived peptide (MOTS‐c) in PCOS and healthy subjects

Ramanjaneya, Manjunath; Jerobin, Jayakumar; Bettahi, Ilham; Bensila, Milin; Aye, Myint Myint; Siveen, Kodappully Sivaraman; Sathyapalan, Thozhukat; Skarulis, Monica C.; Abou‐Samra, Abdul‐Badi; Atkin, Stephen L.

doi:10.1111/cen.14007

Cited by 31 publications

(32 citation statements)

References 43 publications

(80 reference statements)

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“…MOTS-c, an MDP with its sequence located within the coding region for mitochondrial 12S rRNA gene [14], 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 [22,23]. 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 [14,[24][25][26][27].…”

Section: Agingmentioning

confidence: 99%

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

D’Souza

Woodhead

Hedges

et al. 2020

Aging

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Mitochondria putatively regulate the aging process, in part, through the small regulatory peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) that is encoded by the mitochondrial genome. Here we investigated the regulation of MOTS-c in the plasma and skeletal muscle of healthy aging men. Circulating MOTS-c reduced with age, but older (70-81 y) and middle-aged (45-55 y) men had ~1.5-fold higher skeletal muscle MOTS-c expression than young (18-30 y). Plasma MOTS-c levels only correlated with plasma in young men, was associated with markers of slow-type muscle, and associated with improved muscle quality in the older group (maximal leg-press load relative to thigh cross-sectional area). Using small mRNA assays we provide evidence that MOTS-c transcription may be regulated independently of the full length 12S rRNA gene in which it is encoded, and expression is not associated with antioxidant response element (ARE)-related genes as previously seen in culture. Our results suggest that plasma and muscle MOTS-c are differentially regulated with aging, and the increase in muscle MOTS-c expression with age is consistent with fast-to-slow type muscle fiber transition. Further research is required to determine the molecular targets of endogenous MOTS-c in human muscle but they may relate to factors that maintain muscle quality.

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Section: Agingmentioning

confidence: 99%

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

D’Souza

Woodhead

Hedges

et al. 2020

Aging

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“…PCOS was diagnosed according to the Rotterdam criteria (20). Eleven PCOS and 10 healthy volunteers were recruited as reported previously (21,22). Following the collection of overnight fasted blood samples all the subjects underwent a 5-h saline infusion with insulin sensitivity (IS) assessed by a hyperinsulinemic-euglycemic clamp (HIEC) in the final 2 h to determine the glucose disposal rate (M value).…”

Section: Study Subjects and Insulin/intralipid Clamp Protocolmentioning

confidence: 99%

“…The heart rate and inspired/expired gas fractions were monitored continuously using the same instrument used in the training program for each patient (16,23). After the exercise intervention, anthropometric measurements, blood biochemistry, saline, lipid infusions, and HIEC were repeated in these subjects as reported previously (22). Repeat saline studies for each individual were performed immediately after the 3-month interventional exercise phase and the lipid studies performed 1 week later as for the initial saline lipid sequence.…”

Section: Exercise Interventionmentioning

confidence: 99%

Dynamic Changes in Circulating Endocrine FGF19 Subfamily and Fetuin-A in Response to Intralipid and Insulin Infusions in Healthy and PCOS Women

et al. 2020

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Background: The fibroblast growth factors (FGF) 19 subfamily, also referred to as endocrine FGFs, includes FGF19, FGF21, and FGF23 are metabolic hormones involved in the regulation of glucose and lipid metabolism. Fetuin-A is a hepatokine involved in the regulation of beta-cell function and insulin resistance. Endocrine FGFs and fetuin-A are dysregulated in metabolic disorders including obesity, type 2 diabetes, non-alcoholic fatty liver disease and polycystic ovary syndrome (PCOS). Our study was designed to examine the response of endocrine FGFs and fetuin-A to an acute intralipid, insulin infusion and exercise in PCOS and healthy women. Subjects and Measurements: Ten healthy and 11 PCOS subjects underwent 5-h saline infusions with a hyperinsulinemic-euglycemic clamp (HIEC) performed during the final 2 h. One week later, intralipid infusions were undertaken with a HIEC performed during the final 2 h. After an 8 week of exercise intervention the saline, intralipid, and HIEC were repeated. Plasma levels of endocrine FGFs and fetuin-A were measured. Results: Baseline fetuin-A was higher in PCOS women but FGF19, FGF21, and FGF23 did not differ and were unaffected by exercise. Insulin administration elevated FGF21 in control and PCOS, suppressed FGF19 in controls, and had no effects on FGF23 and fetuin-A. Intralipid infusion suppressed FGF19 and increased FGF21. Insulin with intralipid synergistically increased FGF21 and did not have effects on lipid-mediated suppression of FGF19 in both groups. Conclusion: Our study provides evidence for insulin and lipid regulation of endocrine FGFs in healthy and PCOS women, suggesting that FGF family members play a role in lipid and glucose metabolism.

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“…It is possible that the exported MOTS‐c transcript may be cotranslated and translocated to the mitochondria using such mitochondrial‐associated cytoplasmic ribosomes. Work is also in progress to understand cellular cues that induce MOTS‐c expression, and metabolic alterations and inflammation may be key. Similar to HN, MOTS‐c has both intracellular and endocrine roles .…”

Section: Regulatory Peptides Encoded In the Mitochondrial Genome: Newmentioning

confidence: 99%

MOTS‐c: A Mitochondrial‐Encoded Regulator of the Nucleus

Benayoun

Lee

2019

BioEssays

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Mitochondria are increasingly being recognized as information hubs that sense cellular changes and transmit messages to other cellular components, such as the nucleus, the endoplasmic reticulum (ER), the Golgi apparatus, and lysosomes. Nonetheless, the interaction between mitochondria and the nucleus is of special interest because they both host part of the cellular genome. Thus, the communication between genome‐bearing organelles would likely include gene expression regulation. Multiple nuclear‐encoded proteins have been known to regulate mitochondrial gene expression. On the contrary, no mitochondrial‐encoded factors are known to actively regulate nuclear gene expression. MOTS‐c (mitochondrial open reading frame of the 12S ribosomal RNA type‐c) is a recently identified peptide encoded within the mitochondrial 12S ribosomal RNA gene that has metabolic functions. Notably, MOTS‐c can translocate to the nucleus upon metabolic stress (e.g., glucose restriction and oxidative stress) and directly regulate adaptive nuclear gene expression to promote cellular homeostasis. It is hypothesized that cellular fitness requires the coevolved mitonuclear genomes to coordinate adaptive responses using gene‐encoded factors that cross‐regulate the opposite genome. This suggests that cellular gene expression requires the bipartite split genomes to operate as a unified system, rather than the nucleus being the sole master regulator.

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Lipids and insulin regulate mitochondrial‐derived peptide (MOTS‐c) in PCOS and healthy subjects

Cited by 31 publications

References 43 publications

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

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

Dynamic Changes in Circulating Endocrine FGF19 Subfamily and Fetuin-A in Response to Intralipid and Insulin Infusions in Healthy and PCOS Women

MOTS‐c: A Mitochondrial‐Encoded Regulator of the Nucleus

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