bioRxiv Science⌕ Search

bioRxiv · 10.1101/2023.09.07.556663

The effect of lactational low protein diet on skeletal muscle during adulthood and ageing in male and female mouse offspring

Abstract

Sarcopenia is characterised by loss of skeletal muscle mass and function associated with a reduction in muscle fibres. External factors, like exercise and diet, can also influence skeletal muscle mass and contribute to muscle fibre loss. Maternal programming refers to the effect of maternal environmental factors such as nutrition that lead to phenotypic changes in the offspring. Maternal malnutrition has been linked to a reduction in body weight and impaired development of skeletal muscle of the offspring; however, there are no studies that reported the long-term effect of maternal low protein diet on the ageing of skeletal muscles. This study aimed to examine how maternal protein deficiency during lactation affects skeletal muscle development and ageing in the offspring. Pups born from normally fed mothers were lactated by low protein fed mothers. Post-weaning, mice were either maintained on a low protein diet (LPD) or switched to normal protein diet (NPD). Pups born from normally fed mothers and maintained on NPD during lactation and afterwards were used as control. In males, the diet mainly affected the size of the myofibres without major effect on fibre number and led to a reduced grip strength of ageing mice (24 months). Female mice had a lower body and muscle weight at weaning but caught up with control mice at 3 months. During ageing, muscle weight, myofibre number and survival rate of female pups were significantly affected. These findings highlight longitudinal animal research for nutritional programming and the importance of sexual dimorphism in response to challenges. HighlightsO_LIPostnatal low protein diet significantly decreases the survival rate of female but not male mice. C_LIO_LIDuring ageing, female mice fed a low protein diet during lactation have lower muscle weight. C_LIO_LIDuring ageing, female mice fed a low protein diet postnatally maintain their myofibre number. C_LIO_LIMale mice fed a low protein diet postnatally have lower body weight and muscle weight throughout their lifespan. C_LIO_LILow protein diet affects myofibres size of TA muscle of male but not female mice at 3 months of age however this effect is lost during ageing. C_LI

Source connections

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Alameddine, M., Altinpinar, A. E., Ersoy, U., Kanakis, I., Myrtziou-Kanaki, I., E. Ozanne, S., Goljanek-Whysall, K., Vasilaki, A.. 2023-09-12. The effect of lactational low protein diet on skeletal muscle during adulthood and ageing in male and female mouse offspring. https://doi.org/10.1101/2023.09.07.556663

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Rad and Phospholamban are Key Drivers of the Ventricular Adrenergic Response and Stress-Induced Arrhythmia

The adrenergic response is a fundamental mechanism that regulates heart rate (chronotropy), cardiac contractility (inotropy) and relaxation (lusitropy). Adrenergic stress is also a recognized trigger of arrhythmia in disease. Yet, our understanding of the underlying molecular basis remains incomplete. Protein kinase A (PKA) and the calcium/calmodulin-dependent kinase II (CaMKII) phosphorylate multiple targets proposed to participate in the adrenergic response, including the GTP-binding protein Rad, phospholamban (PLB) and ryanodine receptor 2 (RyR2). Here we demonstrate that phosphorylation of both Rad and PLB is necessary for inotropy and lusitropy. We show that changes in cardiac contractility and relaxation are primarily dependent on intracellular calcium handling. Finally, we report that Rad and PLB control stress-induced arrhythmogenesis, despite the phosphorylation of other pro-arrhythmic targets. We have identified the essential molecular components of the adrenergic response, resolving a long-standing debate in cardiac excitation-contraction coupling and refining current models of sympathetic regulation in health and disease.

physiology↗

MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss

Metabolites are increasingly recognized as circulating molecules that regulate physiology, yet the mechanisms that couple intracellular production to organism-wide action remain poorly defined. Using the anorexigenic metabolite Lac-Phe as a tractable system, we identify the orphan transporter MCT6 (SLC16A5) as a physiologic intestinal Lac-Phe exporter. This mechanism controls the extent to which intracellularly synthesized Lac-Phe acquires systemic activity. MCT6 transports Lac-Phe, mediates its cellular efflux, and is required for maintaining its blood levels in mice following strong glycolytic stimuli. Both global and intestinal epithelial-specific deletion of MCT6 confers resistance to metformin-associated weight loss on a high-fat diet. Bypassing the transport defect with exogenous Lac-Phe normalizes the body weight phenotype of MCT6-KO mice. Together, these data connect MCT6 to metformin pharmacology and intestinal lactate metabolism, and more generally underscore the importance of transporter-mediated release in the conversion of an intracellular metabolic state into a circulating metabolite effector.

physiology↗

DEPP1 connects nutrient and oxygen availability to maintenance of muscle mass

Nutrients and oxygen are sensed within the muscle to control growth and disruption of either signal is sufficient to lead to muscle atrophy. While nutrient limitation is sensed via a conserved transcriptional atrophy program (commonly referred to as atrogenes) dictated via the Forkhead box O (FoxO) transcription factors, how low oxygen promotes muscle loss remains unknown. Accordingly, the downstream mechanisms that initiate muscle loss when oxygen and nutrients are limiting are only partly understood. Here, we find Hypoxia Inducible Factor (HIF), the master regulator of our adaptation to low oxygen, is necessary and sufficient to mediate muscle loss under hypoxia in mice. RNA sequencing in skeletal muscle isolated from starved or hypoxic mice identifies Decidual Protein Induced by Progesterone 1 (Depp1), which is induced in skeletal muscle when nutrients or oxygen is limiting via FoxO1 and HIF activation, respectively. Whole body Depp1 loss in mice reduces muscle loss under fasting and hypoxia and skeletal muscle Depp1 overexpression is sufficient to mediate muscle atrophy. Mechanistically, Depp1 localizes to the mitochondria and is necessary to control autophagy activation and mitochondrial degradation in skeletal muscle. Taken together, our studies nominate Depp1 as a new atrogene necessary for muscle loss under multiple atrophy scenarios involving FoxO and HIF.

physiology↗