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Direct or indirect regulation of muscle protein synthesis by energy status?
Moinard, C, Fontaine, E
Clinical nutrition (Edinburgh, Scotland). 2021;(4):1893-1896
Abstract
Muscle protein synthesis (MPS) is a complex and finely-regulated mechanism that plays a key role in muscle homeostasis. Amino acid bioavailability is widely considered a major driver of MPS regulation via mTOR pathway activation. However, recent results suggest that amino acid bioavailability affects cellular energy status. Whatever the tool used to modulate energy status (amino acid depletion or mild mitochondrial uncoupling), a decrease in cellular energy status decreases MPS, without necessarily involving the mTOR pathway. Here we propose that energy status directly regulates one or several energy-consuming step(s) during MPS. This new paradigm modifies our vision of protein metabolism and raises prospects for new advances in therapeutics.
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2.
eIF4E and Interactors from Unicellular Eukaryotes.
Ross-Kaschitza, D, Altmann, M
International journal of molecular sciences. 2020;(6)
Abstract
eIF4E, the mRNA cap-binding protein, is well known as a general initiation factor allowing for mRNA-ribosome interaction and cap-dependent translation in eukaryotic cells. In this review we focus on eIF4E and its interactors in unicellular organisms such as yeasts and protozoan eukaryotes. In a first part, we describe eIF4Es from yeast species such as Saccharomyces cerevisiae, Candida albicans, and Schizosaccharomyces pombe. In the second part, we will address eIF4E and interactors from parasite unicellular species-trypanosomatids and marine microorganisms-dinoflagellates. We propose that different strategies have evolved during evolution to accommodate cap-dependent translation to differing requirements. These evolutive "adjustments" involve various forms of eIF4E that are not encountered in all microorganismic species. In yeasts, eIF4E interactors, particularly p20 and Eap1 are found exclusively in Saccharomycotina species such as S. cerevisiae and C. albicans. For protozoan parasites of the Trypanosomatidae family beside a unique cap4-structure located at the 5'UTR of all mRNAs, different eIF4Es and eIF4Gs are active depending on the life cycle stage of the parasite. Additionally, an eIF4E-interacting protein has been identified in Leishmania major which is important for switching from promastigote to amastigote stages. For dinoflagellates, little is known about the structure and function of the multiple and diverse eIF4Es that have been identified thanks to widespread sequencing in recent years.
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3.
The Interaction between Dietary Selenium Intake and Genetics in Determining Cancer Risk and Outcome.
Kadkol, S, Diamond, AM
Nutrients. 2020;(8)
Abstract
There is considerable interest in the trace element selenium as a possible cancer chemopreventive dietary component, but supplementation trials have not indicated a clear benefit. Selenium is a critical component of selenium-containing proteins, or selenoproteins. Members of this protein family contain selenium in the form of selenocysteine. Selenocysteine is encoded by an in-frame UGA codon recognized as a selenocysteine codon by a regulatory element, the selenocysteine insertion sequence (SECIS), in the 3'-untranslated region of selenoprotein mRNAs. Epidemiological studies have implicated several selenoprotein genes in cancer risk or outcome based on associations between allelic variations and disease risk or mortality. These polymorphisms can be found in or near the SECIS or in the selenoprotein coding sequence. These variations both function to control protein synthesis and impact the efficiency of protein synthesis in response to the levels of available selenium. Thus, an individual's genetic makeup and nutritional intake of selenium may interact to predispose them to acquiring cancer or affect cancer progression to lethality.
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4.
Translational regulation of environmental adaptation in bacteria.
Tollerson, R, Ibba, M
The Journal of biological chemistry. 2020;(30):10434-10445
Abstract
Bacteria must rapidly respond to both intracellular and environmental changes to survive. One critical mechanism to rapidly detect and adapt to changes in environmental conditions is control of gene expression at the level of protein synthesis. At each of the three major steps of translation-initiation, elongation, and termination-cells use stimuli to tune translation rate and cellular protein concentrations. For example, changes in nutrient concentrations in the cell can lead to translational responses involving mechanisms such as dynamic folding of riboswitches during translation initiation or the synthesis of alarmones, which drastically alter cell physiology. Moreover, the cell can fine-tune the levels of specific protein products using programmed ribosome pausing or inducing frameshifting. Recent studies have improved understanding and revealed greater complexity regarding long-standing paradigms describing key regulatory steps of translation such as start-site selection and the coupling of transcription and translation. In this review, we describe how bacteria regulate their gene expression at the three translational steps and discuss how translation is used to detect and respond to changes in the cellular environment. Finally, we appraise the costs and benefits of regulation at the translational level in bacteria.
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5.
Influence of nascent polypeptide positive charges on translation dynamics.
Requião, RD, Barros, GC, Domitrovic, T, Palhano, FL
The Biochemical journal. 2020;(15):2921-2934
Abstract
Protein segments with a high concentration of positively charged amino acid residues are often used in reporter constructs designed to activate ribosomal mRNA/protein decay pathways, such as those involving nonstop mRNA decay (NSD), no-go mRNA decay (NGD) and the ribosome quality control (RQC) complex. It has been proposed that the electrostatic interaction of the positively charged nascent peptide with the negatively charged ribosomal exit tunnel leads to translation arrest. When stalled long enough, the translation process is terminated with the degradation of the transcript and an incomplete protein. Although early experiments made a strong argument for this mechanism, other features associated with positively charged reporters, such as codon bias and mRNA and protein structure, have emerged as potent inducers of ribosome stalling. We carefully reviewed the published data on the protein and mRNA expression of artificial constructs with diverse compositions as assessed in different organisms. We concluded that, although polybasic sequences generally lead to lower translation efficiency, it appears that an aggravating factor, such as a nonoptimal codon composition, is necessary to cause translation termination events.
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6.
Mitochondrial Protein Quality Control Mechanisms.
Jadiya, P, Tomar, D
Genes. 2020;(5)
Abstract
Mitochondria serve as a hub for many cellular processes, including bioenergetics, metabolism, cellular signaling, redox balance, calcium homeostasis, and cell death. The mitochondrial proteome includes over a thousand proteins, encoded by both the mitochondrial and nuclear genomes. The majority (~99%) of proteins are nuclear encoded that are synthesized in the cytosol and subsequently imported into the mitochondria. Within the mitochondria, polypeptides fold and assemble into their native functional form. Mitochondria health and integrity depend on correct protein import, folding, and regulated turnover termed as mitochondrial protein quality control (MPQC). Failure to maintain these processes can cause mitochondrial dysfunction that leads to various pathophysiological outcomes and the commencement of diseases. Here, we summarize the current knowledge about the role of different MPQC regulatory systems such as mitochondrial chaperones, proteases, the ubiquitin-proteasome system, mitochondrial unfolded protein response, mitophagy, and mitochondria-derived vesicles in the maintenance of mitochondrial proteome and health. The proper understanding of mitochondrial protein quality control mechanisms will provide relevant insights to treat multiple human diseases.
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7.
Muscle Protein Synthesis and Whole-Body Protein Turnover Responses to Ingesting Essential Amino Acids, Intact Protein, and Protein-Containing Mixed Meals with Considerations for Energy Deficit.
Gwin, JA, Church, DD, Wolfe, RR, Ferrando, AA, Pasiakos, SM
Nutrients. 2020;(8)
Abstract
Protein intake recommendations to optimally stimulate muscle protein synthesis (MPS) are derived from dose-response studies examining the stimulatory effects of isolated intact proteins (e.g., whey, egg) on MPS in healthy individuals during energy balance. Those recommendations may not be adequate during periods of physiological stress, specifically the catabolic stress induced by energy deficit. Providing supplemental intact protein (20-25 g whey protein, 0.25-0.3 g protein/kg per meal) during strenuous military operations that elicit severe energy deficit does not stimulate MPS-associated anabolic signaling or attenuate lean mass loss. This occurs likely because a greater proportion of the dietary amino acids consumed are targeted for energy-yielding pathways, whole-body protein synthesis, and other whole-body essential amino acid (EAA)-requiring processes than the proportion targeted for MPS. Protein feeding formats that provide sufficient energy to offset whole-body energy and protein-requiring demands during energy deficit and leverage EAA content, digestion, and absorption kinetics may optimize MPS under these conditions. Understanding the effects of protein feeding format-driven alterations in EAA availability and subsequent changes in MPS and whole-body protein turnover is required to design feeding strategies that mitigate the catabolic effects of energy deficit. In this manuscript, we review the effects, advantages, disadvantages, and knowledge gaps pertaining to supplemental free-form EAA, intact protein, and protein-containing mixed meal ingestion on MPS. We discuss the fundamental role of whole-body protein balance and highlight the importance of comprehensively assessing whole-body and muscle protein kinetics when evaluating the anabolic potential of varying protein feeding formats during energy deficit.
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8.
Gut-Muscle AxisExists and May Affect Skeletal Muscle Adaptation to Training.
Przewłócka, K, Folwarski, M, Kaźmierczak-Siedlecka, K, Skonieczna-Żydecka, K, Kaczor, JJ
Nutrients. 2020;(5)
Abstract
Excessive training may limit physiological muscle adaptation through chronic oxidative stress and inflammation. Improper diet and overtraining may also disrupt intestinal homeostasis and in consequence enhance inflammation. Altogether, these factors may lead to an imbalance in the gut ecosystem, causing dysregulation of the immune system. Therefore, it seems to be important to optimize the intestinal microbiota composition, which is able to modulate the immune system and reduce oxidative stress. Moreover, the optimal intestinal microbiota composition may have an impact on muscle protein synthesis and mitochondrial biogenesis and function, as well as muscle glycogen storage. Aproperly balanced microbiome may also reduce inflammatory markers and reactive oxygen species production, which may further attenuate macromolecules damage. Consequently, supplementation with probiotics may have some beneficial effect on aerobic and anaerobic performance. The phenomenon of gut-muscle axis should be continuously explored to function maintenance, not only in athletes.
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9.
It's not just about protein turnover: the role of ribosomal biogenesis and satellite cells in the regulation of skeletal muscle hypertrophy.
Brook, MS, Wilkinson, DJ, Smith, K, Atherton, PJ
European journal of sport science. 2019;(7):952-963
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Abstract
Skeletal muscle has indispensable roles in regulating whole body health (e.g. glycemic control, energy consumption) and, in being central in locomotion, is crucial in maintaining quality-of-life. Therefore, understanding the regulation of muscle mass is of significant importance. Resistance exercise training (RET) combined with supportive nutrition is an effective strategy to achieve muscle hypertrophy by driving chronic elevations in muscle protein synthesis (MPS). The regulation of muscle protein synthesis is a coordinated process, in requiring ribosomes to translate mRNA and sufficient myonuclei density to provide the platform for ribosome and mRNA transcription; as such MPS is determined by both translational efficiency (ribosome activity) and translational capacity (ribosome number). Moreover, as the muscle protein pool expands during hypertrophy, translation capacity (i.e. ribosomes and myonuclei content) could theoretically become rate-limiting such that an inability to expand these pools through ribosomal biogenesis and satellite cell (SC) mediated myonuclear addition could limit growth potential. Simple measures of RNA (ribosome content) and DNA (SC/Myonuclei number) concentrations reveal that these pools do increase with hypertrophy; yet whether these adaptations are a pre-requisite or a limiting factor for hypertrophy is unresolved and highly debated. This is primarily due to methodological limitations and many assumptions being made on static measures or correlative associations. However recent advances within the field using stable isotope tracers shows promise in resolving these questions in muscle adaptation.
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10.
Effects of acute oral feeding on protein metabolism and muscle protein synthesis in individuals with cancer.
van der Meij, BS, De Groot, LM, Deutz, NEP, Engelen, MPKJ
Nutrition (Burbank, Los Angeles County, Calif.). 2019;:110531
Abstract
Weight loss and muscle loss are common in individuals living with cancer, with ≤50% experiencing involuntary weight loss at any time point in their cancer journey, and between 11% and 74% having sarcopenia or significant muscle loss. These changes in body composition are related to poor outcomes such as increased treatment toxicity, impaired quality of life, and reduced survival duration. Poor outcomes are not restricted to those who are underweight with severe weight loss; sarcopenia alone has been shown to be a prognostic marker across all body mass index categories, ranging from underweight to obesity To understand the mechanism of nutrition interventions in cancer and to develop effective future interventions, it is necessary to look at the acute effects of feeding on the response of the body and the ability to reach an anabolic response. The aim of this study was to explore and summarize the emerging evidence on metabolic effects of acute oral interventions on whole body protein kinetics and muscle protein synthesis in individuals with cancer.