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Protein level of the rat homolog to HN, termed rattin (RN), in metabolically-relevant tissues in male S-D rats. A total of 30 mg of rat skeletal muscle (lane 1), liver (lane 2), epididymal fat (lane 3) and hypothalamic protein (lane 4) and 1.5 ng of synthetic RN peptide (lane 5) were loaded. RN protein was detected in muscle, liver and hypothalamus but not in epididymal fat (lane 3). doi:10.1371/journal.pone.0006334.g001
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Decline in insulin action is a metabolic feature of aging and is involved in the development of age-related diseases including Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD). A novel mitochondria-associated peptide, Humanin (HN), has a neuroprotective role against AD-related neurotoxicity. Considering the association between insulin r...
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Context 1
... Sprague2Dawley rats (S- D, Charles River Laboratories) and 9 three-month old Zucker Diabetic Fatty (ZDF) rats (Harlan). Rats were housed in individual cages and subjected to a standard light2dark cycle (12L:12D). Depending on the study group the rats received ICV and IV catheters. For ICV studies, S-D rats were prepared for clamps as described in Fig. 1A. Three weeks before the in vivo studies, catheters were implanted in the third cerebral ventricle [21]. One week before clamp experiments, catheters were placed in the right internal jugular vein and left carotid artery [22]. ZDF rats were allowed to acclimate for 1 wk and glucose levels were monitored for the appearance of diabetes ...
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... for assessment of the basal glucose turnover, and a 120-min pancreatic or hyperinsulinemic clamp period. A primed-continu- ous ICV infusion of HN, F6AHN (total dose of 20 ug), dimerization deficient (DD) HN, STAT-3 inhibitor (75 pmol) , or artificial cerebro-spinal fluid (aCSF) was initiated at t = 0 and maintained throughout the experiment (Fig. 1A) by an infusion pump. Pancreatic insulin-clamp studies (1 mU/kg/min), approx- imating the basal fasting state with circulating insulin levels around 1.4 ng/ml, or euglycemic-hyperinsulinemic clamps (3 mU/kg/ min), corresponding to the post-prandial state with circulating insulin levels around 4.5 ng/ml, were performed in conscious, ...
Context 3
... confirm the presence of rattin (RN), the rat homolog to HN, we analyzed the expression level of RN protein in metabolically relevant tissues including the skeletal muscle, liver, fat and hypothalamus. As demonstrated by western blot (Fig. 1), RN is expressed in muscle, liver and hypothalamus but was not detected in epididymal fat. The observed band for RN in the hypothalamus runs slightly higher than in other tissues. This is consistent with the observation by Tajima et al. [3] who showed that HN derived from lipid-enriched tissues in rodents produces a HN band that is ...
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Citations
... MDPs) (Miller et al., 2020;Miller, Kim, Kumagai, Yen, & Cohen, 2022;Miller et al., 2022). Humanin was initially cloned from the occipital lobe of an AD patient during a cDNA screen for amyloid beta (Aβ) protection and has been reported to attenuate AD pathology through mechanisms similar to those associated with APOE: Aβ reduction, energetics, and cell survival (Guo et al., 2003;Ikonen et al., 2003;Lee et al., 2014;Muzumdar et al., 2009;Park et al., 2013;Tajima et al., 2005;Xu et al., 2006;Zhang et al., 2013). Furthermore, it was reported that mtDNA variant within humanin (rs2854128) was associated with cognitive decline and lower circulating humanin levels (Yen et al., 2018), and a separate report noted levels of humanin associated with longevity in multiple model organisms . ...
The APOE4 allele is recognized as a significant genetic risk factor to Alzheimer's disease (AD) and influences longevity. Nonetheless, some APOE4 carriers exhibit resistance to AD even in advanced age. Humanin, a mitochondrial‐derived peptide comprising 24 amino acids, has variants linked to cognitive resilience and longevity. Our research uncovered a unique humanin variant, P3S, specifically enriched in centenarians with the APOE4 allele. Through in silico analyses and subsequent experimental validation, we demonstrated a strong affinity between humanin P3S and APOE4 . Utilizing an APOE4 ‐centric mouse model of amyloidosis (APP/PS1/ APOE4 ), we observed that humanin P3S significantly attenuated brain amyloid‐beta accumulation compared to the wild‐type humanin. Transcriptomic assessments of mice treated with humanin P3S highlighted its potential mechanism involving the enhancement of amyloid beta phagocytosis. Additionally, in vitro studies corroborated humanin P3S's efficacy in promoting amyloid‐beta clearance. Notably, in the temporal cortex of APOE4 carriers, humanin expression is correlated with genes associated with phagocytosis. Our findings suggest a role of the rare humanin variant P3S, especially prevalent among individuals of Ashkenazi descent, in mitigating amyloid beta pathology and facilitating phagocytosis in APOE4 ‐linked amyloidosis, underscoring its significance in longevity and cognitive health among APOE4 carriers.
... Among the first to be discovered was the humanin gene (HN), which was identified in Nishimoto's lab in 2001 through functional expression screening (Hashimoto et al. 2001). Humanin has been confirmed as a biologically active peptide that, for example, enhances insulin sensitivity (Muzumdar et al. 2009). ...
The aim of this study is to determine the influence of the mitochondrial open-reading-frame of the twelve S rRNA-c (MOTS-c) peptide on pancreatic cell physiology. Moreover, in this study, we examined the changes in MOTS-c secretion and expression under different conditions. Our experiments were conducted using laboratory cell line cultures, specifically the INS-1E and αTC-1 cell lines, which represent β and α pancreatic cells, respectively. As the pancreas is an endocrine organ, we also tested its hormone regulation capabilities. Furthermore, we assessed the secretion of MOTS-c after incubating the cells with glucose and free fatty acids. Additionally, we examined key cell culture parameters such as cell viability, proliferation, and apoptosis. The results obtained from this study show that MOTS-c has a significant impact on the physiology of pancreatic cells. Specifically, it lowers insulin secretion and expression in INS-1E cells and enhances glucagon secretion and expression in αTC-1 cells. Furthermore, MOTS-c affects cell viability and apoptosis. Interestingly, insulin and glucagon affect the MOTS-c secretion as well as glucose and free fatty acids. These experiments clearly show that MOTS-c is an important regulator of pancreatic metabolism, and there are numerous properties of MOTS-c yet to be discovered.
... Children who had failed to recover nutritionally at any point (defined as having a worse nutritional category than at a previous time point or dying) had a lower concentration of the growth factor-binding protein IGFBP3 (−0.22 log 10 pg/ml; 95% CI, −0.33 to −0.10; P = 0.010) after Romano-Wolf correction for multiple hypothesis testing (table S7). Although this analysis should be interpreted with caution because it required a participant to have a subsequent time point to be included in the analysis, it suggests a role for this protein that prolongs the halflife of the insulin-like growth factors and inhibits the positive effect of humanin on insulin sensitivity (20). ...
Severe acute malnutrition (SAM) is the most high-risk form of undernutrition, particularly when children require hospitalization for complications. Complicated SAM is a multisystem disease with high inpatient and postdischarge mortality, especially in children with comorbidities such as HIV; however, the underlying pathogenesis of complicated SAM is poorly understood. Targeted multiplex biomarker analysis in children hospitalized with SAM ( n = 264) was conducted on plasma samples, and inflammatory markers were assessed on stool samples taken at recruitment, discharge, and 12 to 24 and 48 weeks after discharge from three hospitals in Zimbabwe and Zambia. Compared with adequately nourished controls ( n = 173), we found that at baseline, complicated SAM was characterized by systemic, endothelial, and intestinal inflammation, which was exacerbated by HIV infection. This persisted over 48 weeks despite nutritional recovery and was associated with children’s outcomes. Baseline plasma concentrations of vascular endothelial growth factor, glucagon-like peptide-2, and intestinal fatty acid–binding protein were independently associated with lower mortality or hospital readmission over the following 48 weeks. Following principal components analysis of baseline biomarkers, higher scores of a component representing growth factors was associated with greater weight-for-height z score recovery and lower mortality or hospital readmission over the 48 weeks. Conversely, components representing higher gut and systemic inflammation were associated with higher mortality or hospital readmission. These findings highlight the interplay between inflammation, which damages tissues, and growth factors, which mediate endothelial and epithelial regeneration, and support further studies investigating interventions to reduce inflammation and promote epithelial repair as an approach to reducing mortality and improving nutritional recovery.
... 85,86 Humanin treatment in rodents has shown positive effects on their glucose metabolism by improving glucosestimulated insulin secretion and sensitivity. 87,88 Subsequently, six small humanin-like peptides (SHLP) have been identified as MDPs, which are encoded in the ORFs within the same gene in which humanin is located. 89 SHLP-2 and 3 have similar neuro-protective effects as those of humanin, and they improve mitochondrial metabolism and reduce apoptosis and ROS production. ...
Mitochondria function as platforms for bioenergetics, nutrient metabolism, intracellular signaling, innate immunity regulators, and modulators of stem cell activity. Thus, the decline in mitochondrial functions causes or correlates with diabetes mellitus and many aging-related diseases. Upon stress or damage, the mitochondria elicit a series of adaptive responses to overcome stress and restore their structural integrity and functional homeostasis. These adaptive responses to low-level or transient mitochondrial stress promote health and resilience to upcoming stress. Beneficial effects of low-grade mitochondrial stress, termed mitohormesis, have been observed in various organisms, including mammals. Accumulated evidence indicates that treatments boosting mitohormesis have therapeutic potential in various human diseases accompanied by mitochondrial stress. Here, we review multiple cellular signaling pathways and interorgan communication mechanisms through which mitochondrial stress leads to advantageous outcomes. We also discuss the relevance of mitohormesis in obesity, diabetes, metabolic liver disease, aging, and exercise.
... Human aging, usually consistent with mitochondrial dysfunction caused by increased mitophagy and mitokine secretion, initiates crucial stress response mechanisms that might have a wholesome effect [39]. Despite a growing body of evidence indicating that humanin level (in rodents and humans) declines during aging, contributing to age-related diseases, our current study does not support previous research in this area [40,41]. Contrary to what was previously thought, we found that humanin serum levels increase with age, which is consistent with Conte et al. [42]. ...
The discovery of mitochondria-derived peptides (MDPs) has provided a new perspective on mitochondrial function. MDPs encoded by mitochondrial DNA (mtDNA) can act as hormone-like peptides, influencing cell survival and proliferation. Among these peptides, humanin has been identified as a crucial factor for maintaining cell survival and preventing cell death under various conditions. Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy that results from adrenal hormone dysfunction. This study aimed to investigate humanin expression in the adrenal tissue and serum of patients with ACC. For the first time, our study revealed significant reduction in the mRNA expression of humanin in patients with ACC compared to healthy controls. However, no significant changes were observed in the serum humanin levels. Interestingly, we identified a positive correlation between patient age and serum humanin levels and a negative correlation between tumor size and LDL levels. While the impaired expression of humanin in patients with ACC may be attributed to mitochondrial dysfunction, an alternative explanation could be related to diminished mitochondrial copy number. Further investigations are warranted to elucidate the intricate relationship among humanin, mitochondrial function, and ACC pathology.
... Humanin is present in other tissues, including the colon, testes, kidney, pancreas, heart and skeletal muscle, in both rodents and humans (Charununtakorn et al., 2016;Liu et al., 2019). In addition to its tissue distribution, HN is also present in cerebrospinal fluid and seminal fluid (Muzumdar et al., 2009). In response to physiological and pathophysiological stressors, including exercise and metabolic diseases, HN can be produced in the above-mentioned tissues and secreted into the circulation von Walden et al., 2021). ...
... Another possible downstream target of HN is Akt, with HNG, a potent HN analogue with a glycine substitution, increasing phosphorylated Akt (p-Akt) levels in SH-SY5Y human neuroblastoma cells and in the brain of mice (Kim et al., 2016;Xu et al., 2008). Humanin was also reported to improve insulin sensitivity by increasing p-Akt levels in the skeletal muscle of rats (Muzumdar et al., 2009). In particular, given that HN is involved in the activation of Akt signalling and that loss of Akt signalling causes the development of obesity and T2D (Brozinick et al., 2003;Huang et al., 2018;Krook et al., 1998), HN might play a key role in metabolic health via insulin signalling. ...
... Owing to these specific functions, HN is considered a potential treatment to improve/cure symptoms of Alzheimer's disease (Rochette et al., 2020). Research has also shown that exogenous treatment with HN and its analogues can improve the prognosis of metabolic diseases, such as insulin resistance, obesity, diabetes and polycystic ovary syndrome (PCOS), in multiple rodent models (Burtscher et al., 2023;Gong et al., 2015;Muzumdar et al., 2009;. Although promising effects of HN have been reported for in vivo and in vitro experiments, further studies in humans are necessary to understand comprehensively the specific metabolic changes that occur with HN supplementation. ...
Exercise is a powerful non‐pharmacological intervention for the treatment and prevention of numerous chronic diseases. Contracting skeletal muscles provoke widespread perturbations in numerous cells, tissues and organs, which stimulate multiple integrated adaptations that ultimately contribute to the many health benefits associated with regular exercise. Despite much research, the molecular mechanisms driving such changes are not completely resolved. Technological advancements beginning in the early 1960s have opened new avenues to explore the mechanisms responsible for the many beneficial adaptations to exercise. This has led to increased research into the role of small peptides (<100 amino acids) and mitochondrially derived peptides in metabolism and disease, including those coded within small open reading frames (sORFs; coding sequences that encode small peptides). Recently, it has been hypothesized that sORF‐encoded mitochondrially derived peptides and other small peptides play significant roles as exercise‐sensitive peptides in exercise‐induced physiological adaptation. In this review, we highlight the discovery of mitochondrially derived peptides and newly discovered small peptides involved in metabolism, with a specific emphasis on their functions in exercise‐induced adaptations and the prevention of metabolic diseases. In light of the few studies available, we also present data on how both single exercise sessions and exercise training affect expression of sORF‐encoded mitochondrially derived peptides. Finally, we outline numerous research questions that await investigation regarding the roles of mitochondrially derived peptides in metabolism and prevention of various diseases, in addition to their roles in exercise‐induced physiological adaptations, for future studies. image
... HN can enhance insulin sensitivity (Fig. 3). In addition, in the central system, intravenous administration of novel potent HN derivatives enhanced central insulin sensitivity (Muzumdar et al., 2009) (Table 3). Changes in glucose metabolism are closely related to the development of AD. ...
... In the brain, if the insulin-mediated AKT signaling pathway is impaired, the phosphorylation of Ser9 is decreased and the enzymatic activity of glycogen synthase kinase-3β (GSK-3β) is increased, leading to the persistent phosphorylation of Tyr216 (tyrosine site of GSK-3β), which leads to the hyperphosphorylation of tau residues, which are also important pathological features of AD . Moreover, miPs can regulate insulin secretion, sensitivity, and mitochondrial function (Muzumdar et al., 2009;Kuliawat et al., 2013;Cobb et al., 2016). These regulatory sites may be potential therapeutic targets for improving cognitive function in AD (Potenza et al., 2021). ...
... SHLP2 also prevents neuronal cell death caused by lactate dehydrogenase (LDH) leakage in the AD model (Cobb et al., 2016) (Fig. 3, Table 3). Small human Lee et al., 2015;Wu et al., 2022Cobb et al., 2016Muzumdar et al., 2009Zárate et al., 2019Miller et al., 2022bMakarewich et al., 2018Stein et al., 2018Bal et al., 2012Ma et al., 2021Makarewich et al., 2022Kang et al., 2020 Ge mitochondrial ORF over SErine tRNA (SHMOOSE), a mitochondrial miP, participates in brain energy metabolism by regulating gene expression in mitochondria. The level of the SHMOOSE in CSF is related to the pathological features of AD. ...
With the development of modern sequencing techniques and bioinformatics, genomes that were once thought to be noncoding have been found to encode abundant functional micropeptides (miPs), a kind of small polypeptides. Although miPs are difficult to analyze and identify, a number of studies have begun to focus on them. More and more miPs have been revealed as essential for energy metabolism homeostasis, immune regulation, and tumor growth and development. Many reports have shown that miPs are especially essential for regulating glucose and lipid metabolism and regulating mitochondrial function. MiPs are also involved in the progression of related diseases. This paper reviews the sources and identification of miPs, as well as the functional significance of miPs for metabolism-related diseases, with the aim of revealing their potential clinical applications.
... Although the precise mechanism of action of humanin remains to be fully elucidated, it has been established that humanin plays a significant role in the reverse communication process between the mitochondria and the nuclear genome, thereby contributing to the maintenance of cellular homeostasis and integrity [10]. This critical involvement in cellular function has led to the confirmation of humanin's protective role in various diseases and experimental models, including Alzheimer's disease [8,11,12], cardiovascular diseases [13,14], stroke [15,16] and type 2 diabetes mellitus [17]. ...
S14G-humanin (HNG), an analog of the mitochondria-derived peptide humanin, has demonstrated protective effects against various cardiovascular diseases. However, the specific pharmacological effects of HNG in heart failure (HF) have not been previously reported. Therefore, in this study, we aimed to investigate the potential protective effect of HNG in HF using a mouse model. HF was induced in mice through intraperitoneal injection of isoproterenol or transverse aortic constriction, followed by separate administration of HNG to assess its therapeutic impact. Our results revealed that HNG treatment significantly delayed the onset of cardiac dysfunction and structural remodeling in the HF mouse model. Furthermore, HNG administration was associated with reduced infiltration of inflammatory cells, improved myocardial fibrosis, and attenuation of cardiomyocyte apoptosis in the treated cardiac tissues. Additionally, we identified the involvement of the transforming growth factor-beta signaling pathway in the beneficial effects of HNG in isoproterenol-induced HF mice. Collectively, these findings underscore the therapeutic potential of HNG in preventing the progression of HF, as demonstrated in two distinct HF mouse models.
... Humanin is a mitochondria-derived peptide that suppresses neuronal apoptosis, preserves synapses, reduces inflammation, and supports glucose and oxidative metabolism [42]. Plasma humanin decreases with age in humans and mice [43], and upon replenishment, cognition in aged mice is improved [44]. Humanin mRNA in plasma EVs has been found decreased in AD compared to control individuals [45], whereas protein levels of humanin in NDEVs have been found decreased in multiple neuropsychiatric disorders [46,47]. ...
Background
Neuron-derived extracellular vesicles (NDEVs) in blood may be used to derive biomarkers for the effects of exercise in Alzheimer’s disease (AD). For this purpose, we studied changes in neuroprotective proteins proBDNF, BDNF, and humanin in plasma NDEVs from patients with mild to moderate AD participating in the randomized controlled trial (RCT) of exercise ADEX.
Methods
proBDNF, BDNF, and humanin were quantified in NDEVs immunocaptured from the plasma of 95 ADEX participants, randomized into exercise and control groups, and collected at baseline and 16 weeks. Exploratorily, we also quantified NDEV levels of putative exerkines known to respond to exercise in peripheral tissues.
Results
NDEV levels of proBDNF, BDNF, and humanin increased in the exercise group, especially in APOE ε4 carriers, but remained unchanged in the control group. Inter-correlations between NDEV biomarkers observed at baseline were maintained after exercise. NDEV levels of putative exerkines remained unchanged.
Conclusions
Findings suggest that the cognitive benefits of exercise could be mediated by the upregulation of neuroprotective factors in NDEVs. Additionally, our results indicate that AD subjects carrying APOE ε4 are more responsive to the neuroprotective effects of physical activity. Unchanged NDEV levels of putative exerkines after physical activity imply that exercise engages different pathways in neurons and peripheral tissues. Future studies should aim to expand upon the effects of exercise duration, intensity, and type in NDEVs from patients with early AD and additional neurodegenerative disorders.
Trial registration
The Effect of Physical Exercise in Alzheimer Patients (ADEX) was registered in ClinicalTrials.gov on April 30, 2012 with the identifier NCT01681602.
Graphical abstract
... A previous study demonstrated a reduction in humanin concentrations in the hypothalamus, skeletal muscle, and brain with age in mice. 25 An analysis of humanin concentrations in plasma from 693 people of varying ages revealed no signs of evolution ...
