The mitochondrial-targeted peptide therapeutic elamipretide improves cardiac and skeletal muscle function during aging without detectable changes in tissue epigenetic or transcriptomic age [methylation array]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1178658 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The mitochondrial-targeted peptide therapeutic elamipretide improves cardiac and skeletal muscle function during aging without detectable changes in tissue epigenetic or transcriptomic age.
| PRJNA1179982 | ENA
Project description:The mitochondrial-targeted peptide therapeutic elamipretide improves cardiac and skeletal muscle function during aging without detectable changes in tissue epigenetic or transcriptomic age [RNA-seq]
| PRJNA1179985 | ENA
Project description:Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondrial-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. ELAM is proposed to restore mitochondrial bioenergetic function by stabilizing inner membrane structure and increasing oxidative phosphorylation coupling and efficiency. Although ELAM treatment effectively attenuates physiological declines in multiple tissues in rodent aging models, it remains unclear whether these functional improvements correlate with favorable changes in molecular biomarkers of aging. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post- measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways. We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force are significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. However, at the level of gene expression and DNA methylation, ELAM did not produce statistically significant changes in molecular organization and biological age in most treatment groups. Pathway analyses indicated that ELAM treatment showed pro-longevity shifts in gene expression such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation and oxidative phosphorylation, and downregulation of inflammation. Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and heart failure in an aging mouse model, but that these functional improvements occur independently of changes in epigenetic and transcriptomic age. Thus, age-related changes in function may be uncoupled from changes in molecular biological age.
2025-03-14 | GSE280472 | GEO
Project description:Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondrial-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. ELAM is proposed to restore mitochondrial bioenergetic function by stabilizing inner membrane structure and increasing oxidative phosphorylation coupling and efficiency. Although ELAM treatment effectively attenuates physiological declines in multiple tissues in rodent aging models, it remains unclear whether these functional improvements correlate with favorable changes in molecular biomarkers of aging. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post- measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways. We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force are significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. However, at the level of gene expression and DNA methylation, ELAM did not produce statistically significant changes in molecular organization and biological age in most treatment groups. Pathway analyses indicated that ELAM treatment showed pro-longevity shifts in gene expression such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation and oxidative phosphorylation, and downregulation of inflammation. Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and heart failure in an aging mouse model, but that these functional improvements occur independently of changes in epigenetic and transcriptomic age. Thus, age-related changes in function may be uncoupled from changes in molecular biological age.
2025-03-14 | GSE280699 | GEO
Project description:Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondrial-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. ELAM is proposed to restore mitochondrial bioenergetic function by stabilizing inner membrane structure and increasing oxidative phosphorylation coupling and efficiency. Although ELAM treatment effectively attenuates physiological declines in multiple tissues in rodent aging models, it remains unclear whether these functional improvements correlate with favorable changes in molecular biomarkers of aging. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post- measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways. We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force are significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. Despite these improvements, we did not detect statistically significant changes in gene expression or DNA methylation profiles indicative of molecular reorganization or reduced biological age in most ELAM-treated groups. However, pathway analyses revealed that ELAM treatment showed pro-longevity shifts in gene expression such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation and oxidative phosphorylation, and downregulation of inflammation. Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and heart failure in an aging mouse model, but that these functional improvements occur independently of detectable changes in epigenetic and transcriptomic age. Thus, some age-related changes in function may be uncoupled from changes in molecular biological age.
| S-EPMC11565897 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-03-14 | GSE280700 | GEO
Project description:Estrogen improves insulin sensitivity and increases energy expenditure, contributing to sexual dimorphism regarding type 2 diabetes mellitus (T2DM) susceptibility. Estrogen receptor α (ERα) plays a crucial role in mediating estrogen action on glucose and energy homeostasis. However, the underlying mechanisms remain incompletely understood. Here, we found a ligand-independent effect of ERα on the regulation of glucose homeostasis and identified an ERα-derived peptide as a potential insulin sensitizer. Deficiency of ERα but not ERβ in the liver impaired glucose homeostasis in male, female, and ovariectomized (OVX) female mice. Mechanistic studies revealed that ERα promoted hepatic insulin sensitivity by suppressing ubiquitination-induced IRS1 degradation. The ERα 1-280 domain mediated the ligand-independent effect of ERα on insulin sensitivity. Furthermore, we designed a peptide based on ERα 1-280 domain and found that ERα-derived peptide interacted with IRS1, increased IRS1 stability through suppressing its ubiquitination, and enhanced insulin sensitivity. Importantly, administration of ERα-derived peptide into obese mice significantly increased insulin sensitivity, attenuated glucose intolerance, and improved serum lipid profiles. These findings pave the way for the therapeutic intervention of T2DM by targeting the ligand-independent effect of ERα and indicate that ERα-derived peptide is a potential insulin sensitizer for the treatment of T2DM.
2024-04-05 | GSE262841 | GEO
Project description:An estrogen receptor α-derived peptide improves glucose homeostasis during obesity
| PRJNA1093463 | ENA
Project description:Aberrant protein aggregation jeopardize cellular functionality and underlies the development of a myriad of late-onset maladies including Alzheimer’s disease (AD) and Huntington’s disease (HD). Accordingly, molecules that mitigate the toxicity of hazardous protein aggregates are of great interest as potential future therapeutics. Here we asked whether a small peptide, composed of five amino acids (5MER peptide) that was derived from the human pro-inflammatory CD44, could protect model nematodes from the toxicity of aggregative proteins that underlie the development of neurodegenerative disorders in humans. We found that the 5MER peptide mitigates the toxicity that stems from both, the AD-causing Aβ peptide and a stretch of poly-glutamine that is accountable to the development of several disorders including HD, without affecting lifespan. This protection was dependent on the activity of the aging-regulating transcription factors and associated with enhanced Aβ and polyQ35-YFP aggregation. A transcriptomic analysis unveiled that the peptide modulates the expression of various genes including these which are known as protein homeostasis (proteostasis) regulators such as txt-13, and modifiers of proteasome activity. The knockdown of txt-13 protects worms from proteotoxicity to the same extent as the 5MER peptide, suggesting that the peptide activates the transcellular chaperone signaling to promote proteostasis. Together, our results propose that the 5MER peptide should be considered as a component of future therapeutic cocktails for the treatment of neurodegenerative maladies.
2023-12-27 | GSE230640 | GEO
Project description:Mitochondrial dysfunction plays a key pathogenic role in aging skeletal muscle resulting in significant healthcare costs in the developed world. However, there is no pharmacologic treatment to rapidly reverse mitochondrial deficits in the elderly. Here, we demonstrate that a single treatment with the mitochondrial-targeted peptide SS-31 restores in vivo mitochondrial energetics to young levels in aged mice after only one hour. Young (5 month old) and old (27 month old) mice were injected intraperitoneally with either saline or 3 mg kg(-1) of SS-31. Skeletal muscle mitochondrial energetics were measured in vivo one hour after injection using a unique combination of optical and (31) P magnetic resonance spectroscopy. Age-related declines in resting and maximal mitochondrial ATP production, coupling of oxidative phosphorylation (P/O), and cell energy state (PCr/ATP) were rapidly reversed after SS-31 treatment, while SS-31 had no observable effect on young muscle. These effects of SS-31 on mitochondrial energetics in aged muscle were also associated with a more reduced glutathione redox status and lower mitochondrial H2 O2 emission. Skeletal muscle of aged mice was more fatigue resistant in situ one hour after SS-31 treatment, and eight days of SS-31 treatment led to increased whole-animal endurance capacity. These data demonstrate that SS-31 represents a new strategy for reversing age-related deficits in skeletal muscle with potential for translation into human use.
| S-EPMC3772966 | biostudies-literature