An acetylation rheostat for the control of muscle energy homeostasis

In recent years, the role of acetylation has gained ground as an essential modulator of intermediary metabolism in skeletal muscle. Imbalance in energy homeostasis or chronic cellular stress, due to diet, aging, or disease, translate into alterations in the acetylation levels of key proteins which govern bioenergetics, cellular substrate use, and/or changes in mitochondrial content and function. For example, cellular stress induced by exercise or caloric restriction can alter the coordinated activity of acetyltransferases and deacetylases to increase mitochondrial biogenesis and function in order to adapt to low energetic levels. The natural duality of these enzymes, as metabolic sensors and effector proteins, has helped biologists to understand how the body can integrate seemingly distinct signaling pathways to control mitochondrial biogenesis, insulin sensitivity, glucose transport, reactive oxygen species handling, angiogenesis, and muscle satellite cell proliferation/differentiation. Our review will summarize the recent developments related to acetylation-dependent responses following metabolic stress in skeletal muscle.

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Autophagy-related genesatg7andbeclin1are essential for energy metabolism and survival during the larval-to-juvenile transition stage of zebrafish

10.1101/666883 ◽

2019 ◽

Author(s):

Suzan Attia Mawed ◽

Jin Zhang ◽

Fan Ren ◽

Jie Mei

Keyword(s):

Energy Homeostasis ◽

Transition Period ◽

Metabolic Stress ◽

Transition Process ◽

The Body ◽

Molecular Evidence ◽

Exogenous Feeding ◽

Eukaryotic Organisms ◽

Juvenile Development

AbstractHigh mortality is usually observed during the transition from larvae to juvenile in teleost which is related to the transition from endogenous to exogenous feeding. Autophagy is an evolutionary regulated cellular mechanism highly conserved in eukaryotic organisms to maintain energy homeostasis against stress including starvation. To investigate whether autophagy plays a role during the larval-juvenile transition, we generatedatg7andbeclin1zebrafish mutant lines using CRISPR/Cas9 technology. In this study, bothatg7andbeclin1null zebrafish exhibited a normal body confirmation; nevertheless, they completely died around 15 dpf and 9 dpf respectively. During larval-juvenile transition period,atg7andbeclin1mutants were unable to cope with the metabolic stress after yolk absorption at 5 dpf and fail to activate autophagy in response to nutrient restriction, and without external feeding, all mutants died nearly at 8 dpf. Dramatic defects in the intestine architecture and metabolic functions in the liver were observed even though providing larvae with an external food supply, suggesting that autophagy isn’t only important during yolk depletion but also within food plenty. Treatment with rapamycin, an activator of autophagy, could effectively extend the survival time of bothatg7andbeclin1null zebrafish through lowering the metabolic rate while it couldn’t activate autophagy in mutants via the canonical pathway. Our findings provided a molecular evidence for the physiological, histological and metabolic changes that occur during the transition process from the larval to the juvenile stages and the chief role of autophagy on the body metabolism during these turning milestones.Author summaryZebrafishDanio reriohas emergrd one of the most powerful research models for studying genes expression during early embryogenesis and postnatal development. On the basis of the cell mechanisms, Macroautphagy, a natural regulated pathway disassembles unnecessary or dysfunctional components orchestrated by more than 36 autophagy related-genes conserved from yeast to mammals. Among those genes areatg7andbeclin1which have been proved to play an important role in regulating post natal development in some mammals however their roles during zebrafish development still unedited. During this research, CRISPER/CAS9 were adopted to knowatg7andbeclin1knockout effects on the mutants’ metabolism during shifting from maternal yolk acquisition to exogenous feeding and the role of autophagy during the larvae to pre-juvenile development. Herein, we found out that larvae couldn’t abandon autophagy in both fasting and feeding conditions as larvae died earlier before pre-juvenile development despite feeding declaring the importance of autophagy not only to provide the cell with essential nutrients during starvation but also to get rid of cargos inside the eukaryotic cells. Briefly, if the larvae didn’t recycle those cargos due to autophagy perturbations, they will die despite providing suitable conditions including food and acclimatization.

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POPDC proteins and cardiac function

Biochemical Society Transactions ◽

10.1042/bst20190249 ◽

2019 ◽

Vol 47 (5) ◽

pp. 1393-1404 ◽

Cited By ~ 4

Author(s):

Thomas Brand

Keyword(s):

Potential Role ◽

Striated Muscle ◽

Short Review ◽

Effector Proteins ◽

Muscle Disease ◽

Disease Genes ◽

Protein Protein Interaction ◽

Interaction Partners ◽

And Function

Abstract The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein–protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.

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Essential Role of Septin 7 in Skeletal Muscle Structure and Function

Biophysical Journal ◽

10.1016/j.bpj.2019.11.1500 ◽

2020 ◽

Vol 118 (3) ◽

pp. 258a

Author(s):

Laszlo Csernoch ◽

Mónika Gönczi ◽

Zsolt Ráduly ◽

László Szabó ◽

Nóra Dobrosi ◽

...

Keyword(s):

Skeletal Muscle ◽

Essential Role ◽

Structure And Function ◽

Muscle Structure ◽

And Function

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The Recent Understanding of the Neurotrophin's Role in Skeletal Muscle Adaptation

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/201696 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 51

Author(s):

Kunihiro Sakuma ◽

Akihiko Yamaguchi

Keyword(s):

Skeletal Muscle ◽

Neuromuscular Disorders ◽

Muscle Fibers ◽

Brain Disorders ◽

Muscle Adaptation ◽

Bdnf Mrna ◽

Pathological Conditions ◽

Development And Differentiation ◽

And Function

This paper summarizes the various effects of neurotrophins in skeletal muscle and how these proteins act as potential regulators of the maintenance, function, and regeneration of skeletal muscle fibers. Increasing evidence suggests that this family of neurotrophic factors influence not only the survival and function of innervating motoneurons but also the development and differentiation of myoblasts and muscle fibers. Muscle contractions (e.g., exercise) produce BDNF mRNA and protein in skeletal muscle, and the BDNF seems to play a role in enhancing glucose metabolism and may act for myokine to improve various brain disorders (e.g., Alzheimer's disease and major depression). In adults with neuromuscular disorders, variations in neurotrophin expression are found, and the role of neurotrophins under such conditions is beginning to be elucidated. This paper provides a basis for a better understanding of the role of these factors under such pathological conditions and for treatment of human neuromuscular disease.

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Abstract 112: A Pathological Role of Endothelial p53 in the Regulation of Endothelial Function and Glucose Metabolism

Circulation Research ◽

10.1161/res.113.suppl_1.a112 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Masataka YOKOYAMA ◽

Yoshio KOBAYASHI ◽

Tohru MINAMINO

Keyword(s):

Skeletal Muscle ◽

Endothelial Cell ◽

Glucose Metabolism ◽

Endothelial Function ◽

Mitochondrial Biogenesis ◽

Glucose Transporter ◽

Diabetic Patients ◽

Glucose Transporter 1 ◽

P53 Activation

Cellular senescence is a state of irreversible growth arrest induced by various stresses such as oncogenic stimuli. This response is controlled by negative regulators of the cell cycle like the p53 tumor suppressor protein. Accumulating evidence has suggested a role of p53 activation in various age-associated conditions including atherosclerosis, heart failure and diabetes. Here we show that endothelial p53 activation plays a pathological role in the regulation of endothelial function and glucose metabolism under diabetic conditions. Endothelial expression of p53 was markedly up-regulated in a streptozotocin-induced diabetes model. Endothelial function such as acetylcholine-dependent vasodilatation was markedly impaired in this model. Although hyperglycemia was not altered, impairment of endothelial function was significantly improved in mice with endothelial cell-specific p53 deficiency. In same way, p53 was markedly activated in ischemic vessels, and endothelial p53 deficiency enhanced ischemia-induced angiogenesis. Mechanistically, endothelial p53 up-regulated the expression of PTEN that negatively regulated the Akt-eNOS pathway, and therefore disruption of p53 improved endothelial dysfunction. We also found that endothelial p53 was markedly activated, and the Akt-eNOS pathway was attenuated in a diet-induced obesity model. Disruption of endothelial p53 activation improved dietary inactivation of eNOS that up-regulated the expression of PGC-1α in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Inhibition of endothelial p53 also improved dietary impairment of glucose transport into skeletal muscle by up-regulating endothelial expression of glucose transporter 1. Consequently, mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation compared with control littermates. These results indicate that endothelial p53 negatively regulates endothelium-dependent vasodilatation, ischemia-induced angiogenesis, and mitochondrial biogenesis by inhibiting the Akt-eNOS pathway and suggest that inhibition of endothelial p53 could be a novel therapeutic target in diabetic patients.

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Recent advances in understanding the role of FOXO3

F1000Research ◽

10.12688/f1000research.15258.1 ◽

2018 ◽

Vol 7 ◽

pp. 1372 ◽

Cited By ~ 18

Author(s):

Renae J. Stefanetti ◽

Sarah Voisin ◽

Aaron Russell ◽

Séverine Lamon

Keyword(s):

Cell Cycle ◽

Skeletal Muscle ◽

Protein Turnover ◽

Genetic Basis ◽

The Body ◽

Biological Processes ◽

Forkhead Box ◽

Protein Pool

The forkhead box O3 (FOXO3, or FKHRL1) protein is a member of the FOXO subclass of transcription factors. FOXO proteins were originally identified as regulators of insulin-related genes; however, they are now established regulators of genes involved in vital biological processes, including substrate metabolism, protein turnover, cell survival, and cell death. FOXO3 is one of the rare genes that have been consistently linked to longevity in in vivo models. This review provides an update of the most recent research pertaining to the role of FOXO3 in (i) the regulation of protein turnover in skeletal muscle, the largest protein pool of the body, and (ii) the genetic basis of longevity. Finally, it examines (iii) the role of microRNAs in the regulation of FOXO3 and its impact on the regulation of the cell cycle.

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A Triple Threat? The Role of Diet, Nutrition, and the Microbiota in T1D Pathogenesis

Frontiers in Nutrition ◽

10.3389/fnut.2021.600756 ◽

2021 ◽

Vol 8 ◽

Author(s):

Emma E. Hamilton-Williams ◽

Graciela L. Lorca ◽

Jill M. Norris ◽

Jessica L. Dunne

Keyword(s):

Beta Cell ◽

Intestinal Microbiota ◽

Beta Cell Function ◽

Cell Function ◽

The Body ◽

Islet Autoimmunity ◽

Potential Mechanism ◽

Modifiable Factors ◽

And Function

In recent years the role of the intestinal microbiota in health and disease has come to the forefront of medical research. Alterations in the intestinal microbiota and several of its features have been linked to numerous diseases, including type 1 diabetes (T1D). To date, studies in animal models of T1D, as well as studies in human subjects, have linked several intestinal microbiota alterations with T1D pathogenesis. Features that are most often linked with T1D pathogenesis include decreased microbial diversity, the relative abundance of specific strains of individual microbes, and altered metabolite production. Alterations in these features as well as others have provided insight into T1D pathogenesis and shed light on the potential mechanism by which the microbiota plays a role in T1D pathogenesis, yet the underlying factors leading to these alterations remains unknown. One potential mechanism for alteration of the microbiota is through diet and nutrition. Previous studies have shown associations of diet with islet autoimmunity, but a direct contributing factor has yet to be identified. Diet, through introduction of antigens and alteration of the composition and function of the microbiota, may elicit the immune system to produce autoreactive responses that result in the destruction of the beta cells. Here, we review the evidence associating diet induced changes in the intestinal microbiota and their contribution to T1D pathogenesis. We further provide a roadmap for determining the effect of diet and other modifiable factors on the entire microbiota ecosystem, including its impact on both immune and beta cell function, as it relates to T1D. A greater understanding of the complex interactions between the intestinal microbiota and several interacting systems in the body (immune, intestinal integrity and function, metabolism, beta cell function, etc.) may provide scientifically rational approaches to prevent development of T1D and other childhood immune and allergic diseases and biomarkers to evaluate the efficacy of interventions.

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MiR 208a Regulates Mitochondrial Biogenesis in Metabolically Challenged Cardiomyocytes

Cells ◽

10.3390/cells10113152 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3152

Author(s):

Naveen Mekala ◽

Jacob Kurdys ◽

Alexis Paige Vicenze ◽

Leana Rose Weiler ◽

Carmen Avramut ◽

...

Keyword(s):

Mitochondrial Biogenesis ◽

Protein Trafficking ◽

Cardiac Contractility ◽

Metabolic Stress ◽

Mitochondrial Translation ◽

Human Cardiomyocytes ◽

Bioenergetic Metabolism ◽

Mitochondrial Defects ◽

And Function ◽

High Albumin

Metabolic syndrome increases the risk for cardiovascular disease including metabolic cardiomyopathy that may progress to heart failure. The decline in mitochondrial metabolism is considered a critical pathogenic mechanism that drives this progression. Considering its cardiac specificity, we hypothesized that miR 208a regulates the bioenergetic metabolism in human cardiomyocytes exposed to metabolic challenges. We screened in silico for potential miR 208a targets focusing on mitochondrial outcomes, and we found that mRNA species for mediator complex subunit 7, mitochondrial ribosomal protein 28, stanniocalcin 1, and Sortin nexin 10 are rescued by the CRISPR deletion of miR 208a in human SV40 cardiomyocytes exposed to metabolic challenges (high glucose and high albumin-bound palmitate). These mRNAs translate into proteins that are involved in nuclear transcription, mitochondrial translation, mitochondrial integrity, and protein trafficking. MiR 208a suppression prevented the decrease in myosin heavy chain α isoform induced by the metabolic stress suggesting protection against a decrease in cardiac contractility. MiR 208a deficiency opposed the decrease in the mitochondrial biogenesis signaling pathway, mtDNA, mitochondrial markers, and respiratory properties induced by metabolic challenges. The benefit of miR 208a suppression on mitochondrial function was canceled by the reinsertion of miR 208a. In summary, miR 208a regulates mitochondrial biogenesis and function in cardiomyocytes exposed to diabetic conditions. MiR 208a may be a therapeutic target to promote mitochondrial biogenesis in chronic diseases associated with mitochondrial defects.

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THE MAIN EXOGENOUS AND ENDOGENOUS FACTORS THAT CAN AFFECT THE MORPHOFUNCTIONAL CHARACTERISTICS OF THE THYROID GLAND (LITERATURE REVIEW)

Reports of Vinnytsia National Medical University ◽

10.31393/reports-vnmedical-2018-22(4)-32 ◽

2018 ◽

Vol 22 (4) ◽

pp. 760-765

Author(s):

О.І. Tiron

Keyword(s):

Thyroid Gland ◽

Thermal Injury ◽

Environmental Temperature ◽

Environmental Chemicals ◽

The Body ◽

Endogenous Factors ◽

Temperature Irradiation ◽

Excessive Consumption ◽

And Function

Despite the important role of the thyroid gland in regulating the functions of the body, the gland is quite sensitive to the adverse effects of various factors on the body. The purpose of the work is to analyze modern sources of scientific literature devoted to the study of the influence of exo- and endogenous factors on the morpho-functional properties of the thyroid gland. Literary data on the influence on the thyroid gland of various environmental chemicals, insufficient or excessive consumption of iodine and selenium, vitamin D deficiency, exposure to pharmaceuticals, smoking, environmental temperature, irradiation, infections, stress, as well as factors of the internal environment, such as atherosclerosis and pregnancy. There are a small number of modern scientific studies concerning the influence on the structure and function of the thyroid gland consequences of thermal injury of the skin.

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Induction of mitochondrial heat shock proteins and mitochondrial biogenesis in endothelial cells upon acute methylglyoxal stress: Evidence for hormetic autofeedback

10.1101/2021.11.30.470545 ◽

2021 ◽

Author(s):

Ruben Bulkescher ◽

Thomas Fleming ◽

Claus Rodemer ◽

Rebekka Medert ◽

Marc Freichel ◽

...

Keyword(s):

Endothelial Cells ◽

Heat Shock ◽

Heat Shock Proteins ◽

Mitochondrial Biogenesis ◽

Metabolic Flux ◽

Metabolic Stress ◽

Oxidative Capacity ◽

Mitochondrial Proteins ◽

Shock Proteins

Increased metabolic flux produces potentially harmful side-products, such as reactive dicarbonyl and oxygen species. The reactive dicarbonly methylglyoxal (MG) can impair oxidative capacity, which is downregulated in type 2 diabetes. Heat shock proteins (HSPs) of subfamily A (Hsp70s) promote ATP-dependent processing of damaged proteins during MG exposure which also involve mitochondrial proteins. Since the protection of mitochondrial proteins could promote higher production of reactive metabolites due to increased substrate flux, tight regulation of HspA-mediated protein handling is important. We hypothesized that stress-inducible HspAs (HspA1A/HspA1B) are pivotal for maintaining mitochondrial biogenesis during acute MG-stress. To analyze the role of stress-inducible HspA1A/HspA1B for maintenance of mitochondrial homeostasis during acute MG exposure, we knocked out HSPA1A/HSPA1B in mouse endothelial cells. HSPA1A/HSPA1B KO cells showed upregulation of the mitochondrial chaperones HspA9 (mitochondrial Hsp70/mortalin) and HspD1 (Hsp60) as well as induction of mitochondrial biogenesis upon MG exposure. Increased mitochondrial biogenesis was reflected by elevated mitochondrial branching, total count and area as well as by upregulation of mitochondrial proteins and corresponding transcription factors. Our findings suggest that mitochondrial HspA9 and HspD1 promote mitochondrial biogenesis during acute MG stress, which is counterregulated by HspA1A/HspA1B to prevent mitochondrial overstimulation and to maintain balanced oxidative capacity under metabolic stress conditions. These data support an important role of HSPs in MG-induced hormesis.

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