Abstract

Accurate translation of genes into proteins is critical to organism fitness, and errors in this process are usually detrimental and cause proteotoxic stress. Mistranslation occurs when the amino acid that is incorporated into the nascent polypeptide chain does not match what is dictated by the genetic code. Valine-to-serine (V→S) and threonine-to-serine (T→S) mistranslating models of the fruit fly Drosophila melanogaster have demonstrated a surprising, sex-specific increase in virgin female longevity. We predict that the added stressor of reproduction would eliminate this mistranslation-induced lifespan increase since females prioritize reproductive tissues over somatic tissues, and proteotoxic stress would therefore lead to higher protein damage and cell death in the soma of mated females. We measured the impact of reproduction on V→S and T→S mistranslating D. melanogaster by measuring longevity, egg laying, and fecundity. Counter to our prediction, both V→S and T→S mistranslation led to a sex-specific increase in mated female longevity compared with nonmistranslating controls. Additionally, the risk of death decreased for mated females with mistranslation, beyond the pure additive benefits of mistranslation alone. These effects could not be explained by reduced egg laying or fertilization rates in mistranslating females. Thus, we find that the added proteotoxic stress caused by mistranslation does not exacerbate the detrimental effects of reproduction and instead can ameliorate lifespan decreases due to female reproduction.

Abstract

The heart is a highly energy-demanding organ that depends on metabolic flexibility to adjust substrate utilization in response to changes in nutrient availability, endocrine signals, and energetic demands. Accumulating evidence demonstrates that dietary patterns are key determinants of myocardial metabolic homeostasis, affecting substrate selection, mitochondrial function, nutrient-sensing pathways, and long-term transcriptional and epigenetic regulation. This review analyzes the molecular mechanisms through which diet regulates cardiac metabolism and explores how chronic nutritional exposures influence the myocardial energetic phenotype. The physiological regulation of cardiac substrate utilization is described, with emphasis on fatty acids, glucose, ketone bodies, and branched-chain amino acids, underscoring the importance of metabolic flexibility in sustaining cardiac efficiency. The regulation of substrate transport and oxidation is examined, including the roles of the carnitine shuttle, insulin signaling, AMPK, mTOR, PPARα–PGC-1α, SIRT3, and other nutrient-sensing networks that coordinate mitochondrial ATP production. The effects of dietary composition and meal timing, such as caloric restriction and intermittent fasting, are discussed as modulators of myocardial metabolism. The adverse effects of chronic nutrient excess are reviewed, including lipotoxicity, glucotoxicity, insulin resistance, mitochondrial dysfunction, oxidative stress, pseudo-hypoxia, fetal metabolic reprogramming, and maladaptive cardiac remodeling. Recent findings on the gut–heart axis, microbiota-derived metabolites, circadian regulation, and metabolic–epigenetic interactions are also considered. Overall, current evidence supports the view that diet is an important and potentially modifiable regulator of the cardiac metabolic phenotype. Advancing the understanding of diet–metabolism interactions may enable the development of targeted nutritional strategies to maintain metabolic flexibility, enhance cardiac bioenergetics, and prevent the progression of heart failure and other cardiometabolic diseases.

Abstract

Insulin resistance (IR) has emerged as a risk factor for lactation insufficiency and delays the onset of milk secretion after childbirth, termed secretory activation (SA). This may cause inadequate infant weight gain and early breastfeeding cessation. However, the mechanisms underlying delayed SA in insulin resistant women are unknown. To investigate this, we characterized the mammary transcriptomes and IR-related hormones of 75 breastfeeding women with healthy term infants during postpartum days 1-5. Participants were divided into IR tertiles based on plasma leptin-to-adiponectin ratio measurements. Those in the highest tertile had later SA onset with greater neonatal weight loss during postpartum days 1-5. Transcriptomic analysis on postpartum day 2 (n=4 high IR vs. n=8 low IR participants) showed transient suppression of mammary insulin and prolactin signaling genes, increased pro-inflammatory gene expression and altered expression of >200 mammary mitochondrial genes. These alterations were absent on postpartum days 3-5. Cultured mammary epithelial cells (MECs) treated with insulin showed upregulation of prolactin signaling and oxidative phosphorylation (OXPHOS) genes, with imaging and bioenergetic studies demonstrating that insulin promotes mitochondrial biogenesis and OXPHOS. Thus, our findings delineate roles for insulin in mammary bioenergetics and highlight mitochondrial dysfunction as a mechanism for delayed SA in insulin resistant women.

Highlights

•Intermittent fasting induces sympathetic innervation in visceral white adipose tissue

•Increased sympathetic innervation is mediated by the NRG4-ERBB4 pathway

•NRG4 expression positively correlates with browning genes in human adipose tissue

Summary

Intermittent fasting (IF) improves metabolic health, in part by remodeling white adipose tissue (WAT), yet the underlying mechanisms remain elusive. Here, we show that IF induces coordinated neurovascular remodeling in visceral WAT, marked by increased angiogenesis and sympathetic innervation. Using tissue clearing and three-dimensional imaging, we find that a 16-week IF regimen increases vascular density and sympathetic nerve fiber branching in perigonadal WAT. Transcriptomic profiling reveals the upregulation of neurotrophic factors, including neuregulin 4 (Nrg4), and browning-associated gene programs. WAT explants from IF-treated mice promote neurite branching in SH-SY5Y neuron-like cells, an effect blunted by ErbB inhibition. In vivo ErbB inhibition further attenuates IF-induced sympathetic remodeling. Human visceral adipose RNA-seq analysis shows a strong positive correlation between NRG4 expression and browning gene signatures. These findings support NRG4-ErbB signaling as a contributor to sympathetic remodeling, linking adipose neurotrophic signaling to metabolic benefits and therapeutic potential in obesity-related disorders.

https://www.sciencedirect.com/science/article/pii/S0531556526002445?via%3Dihub

Highlights

• • Aging does not impair intrinsic mTORC1 activation in response to mechanical tension in skeletal muscle.
• • Passive stretch robustly stimulates mTORC1 signaling similarly in adult and old muscle ex vivo.
• • JNK-SMAD2-L signaling sensitivity to mechanical loading is significantly reduced with aging.
• • Aging may selectively affect tension-sensitive transcriptional pathways rather than translational signaling.
• • Age-related anabolic resistance may be driven by systemic factors rather than intrinsic mechanotransduction deficits.

Abstract

Introduction

Aging is associated with impaired skeletal muscle mass and function, often attributed to reduced sensitivity to anabolic stimuli. This study investigated whether aging influences the sensitivity of key anabolic signaling pathways to mechanical tension development in skeletal muscle.

Methods

Using an ex vivo model, extensor digitorum longus (EDL) muscles from adult (16 weeks) and old (24 months) female mice were subjected to a standardized passive stretch protocol, with contralateral muscles serving as controls. During recovery, phosphorylation of proteins related to downstream mTORC1 and JNK–SMAD2-L signaling were assessed by immunoblotting.

Results

Passive stretch significantly increased phosphorylation of mTORC1-related proteins (mTOR, p70S6K, rpS6, and 4E-BP1) in both adult and old muscles, with no significant differences between age groups, indicating preserved mTORC1 signaling sensitivity to mechanical tension with aging. In contrast, the magnitude of activation of JNK and SMAD2-L signaling was attenuated in old muscles.

Discussion

Our findings reveal that mechanosensitive anabolic signaling is differentially affected by aging. While the intrinsic capacity for mTORC1 activation in response to mechanical tension appears to be preserved with aging, JNK–SMAD2L signaling exhibits reduced mechanosensitivity in aged muscle. This divergence suggests that aging selectively impairs tension-sensitive transcriptional pathways, potentially constraining muscle remodeling despite preserved translational signaling capacity. These findings further imply that age-related deficits observed in vivo may, at least in part, arise from systemic influences rather than intrinsic defects adhering to mTORC1 mechanotransduction.

ABSTRACT

Background

In population studies, high protein, particularly high animal protein, intake is associated with an increased risk of developing type 2 diabetes. Results from preclinical studies suggest this association might be mediated by branched-chain and other essential amino acids.

Objective

Interrogate putative mechanisms linking high protein intake and diabetes risk.

Methods

We conducted a randomized, cross-over, single-meal study in people with overweight/obesity to compare the effects of a standard meal (∼18 g protein/15% meal energy) and high protein meals (∼28 g protein/22% meal energy) enriched with protein from either animal (n=21) or plant (n=21) sources on postprandial plasma amino acid, glucose, and key glucoregulatory hormone concentrations (180-min area-under-the-curve).

Results

Postprandial plasma amino acids were higher after the high-protein meals than the standard (STD) meal, with greater increases (all p<0.05) after the high animal protein (HAP) than the high plant protein (HPP) meal in total essential (HAP vs STD, 28±3%; HPP vs STD, 19±3%; mean±SEM) and total branched-chain (HAP vs STD, 36±3%; HPP vs STD, 24±3%), but not total (all) amino acids. Compared with the STD meal, both the HAP and HPP meals resulted in lower plasma glucose (HAP vs STD, -4.3±2.1%; HPP vs STD, -5.2±1.5%) and higher glucagon (HAP vs STD, 48±12%; HPP vs STD, 44±13%), glucagon-like peptide 1 (HAP vs STD, 23±6%; HPP vs STD, 30±12%), and insulin in relationship to glucose, without differences between the HAP and HPP meals.

Conclusions

Both the amount and type of protein are determinants of postprandial plasma amino acid concentrations, but only the amount, not the type of protein is a determinant of plasma glucoregulatory hormone and glucose concentrations. Therefore, essential and branched-chain amino acids are not important regulators of postprandial glucose homeostasis. Non-protein dietary or non-dietary factors likely mediate differential effects of high animal and high plant protein intake on glucose metabolism.

https://www.sciencedirect.com/science/article/abs/pii/S1568163726002631?via%3Dihub

Highlights

• • Deficient muscle-specific strength is a key component of sarcopenia
• • This review analyses the effects of various interventions in older adults
• • Resistance exercise significantly improved muscle-specific strength
• • Aerobic exercise, concurrent training, and nutritional supplement were ineffective
• • Findings could help identify the best strengthening strategies in older people

Abstract

Purpose

Deficient muscle-specific strength has been recognized as a key component of sarcopenia. However, the impact of various interventions on muscle-specific strength has not been systematically reviewed. This study aims to provide a systematic summary of research examining the effects of exercise, nutrition, and other interventions on muscle-specific strength in older adults.

Methods

Randomized controlled trials (RCTs) were identified through comprehensive searches of major databases. Eligible studies included adults aged 60 years or older, with interventions lasting at least 8 weeks. Studies were required to assess muscle strength normalized by muscle mass. Standardized mean differences (SMDs) were calculated using random-effects meta-analyses, and heterogeneity was evaluated using I² statistics.

Results

A total of 41 RCTs with 3,141 participants were included in the analysis. Interventions included resistance exercise, nutritional supplementation, aerobic exercise, concurrent training, combined exercise and nutrition, caloric restriction, and other therapies. Resistance exercise significantly improved muscle-specific strength (SMD = 0.61, 95% confidence interval: 0.27 to 0.94), although heterogeneity was observed (I² = 81%). In contrast, interventions such as aerobic exercise, concurrent training, combined exercise and nutrition, and nutritional supplementation did not lead to significant improvements in muscle-specific strength. High heterogeneity was observed across all included studies.

Conclusions

Resistance exercise is the most effective intervention for improving muscle-specific strength in older adults. The effects of other interventions, such as nutritional supplementation and aerobic exercise, remain inconclusive. Further well-designed RCTs exploring diverse exercise regimens and nutritional interventions are needed to confirm these findings and identify the most effective strategies for enhancing muscle-specific strength in older populations.