Does skeletal muscle have an ‘epi’‐memory? The role of epigenetics in nutritional programming,metabolic disease,aging and exercise

Skeletal muscle mass, quality and adaptability are fundamental in promoting muscle performance, maintaining metabolic function and supporting longevity and healthspan. Skeletal muscle is programmable and can ‘remember’ early‐life metabolic stimuli affecting its function in adult life. In this review, the authors pose the question as to whether skeletal muscle has an ‘epi’‐memory? Following an initial encounter with an environmental stimulus, we discuss the underlying molecular and epigenetic mechanisms enabling skeletal muscle to adapt, should it re‐encounter the stimulus in later life. We also define skeletal muscle memory and outline the scientific literature contributing to this field. Furthermore, we review the evidence for early‐life nutrient stress and low birth weight in animals and human cohort studies, respectively, and discuss the underlying molecular mechanisms culminating in skeletal muscle dysfunction, metabolic disease and loss of skeletal muscle mass across the lifespan. We also summarize and discuss studies that isolate muscle stem cells from different environmental niches in vivo (physically active, diabetic, cachectic, aged) and how they reportedly remember this environment once isolated in vitro. Finally, we will outline the molecular and epigenetic mechanisms underlying skeletal muscle memory and review the epigenetic regulation of exercise‐induced skeletal muscle adaptation, highlighting exercise interventions as suitable models to investigate skeletal muscle memory in humans. We believe that understanding the ‘epi’‐memory of skeletal muscle will enable the next generation of targeted therapies to promote muscle growth and reduce muscle loss to enable healthy aging.     

Exercise, brain, and cognition across the life span

This is a brief review of current evidence for the relationships between physical activity and exercise and the brain and cognition throughout the life span in non-pathological populations. We focus on the effects of both aerobic and resistance training and provide a brief overview of potential neurobiological mechanisms derived from non-human animal models. Whereas research has focused primarily on the benefits of aerobic exercise in youth and young adult populations, there is growing evidence that both aerobic and resistance training are important for maintaining cognitive and brain health in old age. Finally, in these contexts, we point out gaps in the literature and future directions that will help advance the field of exercise neuroscience, including more studies that explicitly examine the effect of exercise type and intensity on cognition, the brain, and clinically significant outcomes. There is also a need for human neuroimaging studies to adopt a more unified multi-modal framework and for greater interaction between human and animal models of exercise effects on brain and cognition across the life span.     

Review: Animal model and the current understanding of molecule dynamics of adipogenesis

Among several potential animal models that can be used for adipogenic studies, Wagyu cattle is the one that presents unique molecular mechanisms underlying the deposit of substantial amounts of intramuscular fat. As such, this review is focused on current knowledge of such mechanisms related to adipose tissue deposition using Wagyu cattle as model. So abundant is the lipid accumulation in the skeletal muscles of these animals that in many cases, the muscle cross-sectional area appears more white (adipose tissue) than red (muscle fibers). This enhanced marbling accumulation is morphologically similar to that seen in numerous skeletal muscle dysfunctions, disease states and myopathies; this might indicate cross-similar mechanisms between such dysfunctions and fat deposition in Wagyu breed. Animal models can be used not only for a better understanding of fat deposition in livestock, but also as models to an increased comprehension on molecular mechanisms behind human conditions. This revision underlies some of the complex molecular processes of fat deposition in animals.     

The diabetic vasculature: Physiological mechanisms of dysfunction and influence of aerobic exercise training in animal models

Diabetes mellitus (DM) is associated with a number of complications of which chronic vascular complications are undoubtedly the most complex and significant consequence. With a significant impact on health care, 50–80% of people with diabetes die of cardiovascular disease (including coronary artery disease, stroke, peripheral vascular disease and other vascular disease), making it the major cause of morbidity and mortality in diabetic patients. A healthy lifestyle is essential in the management of DM, especially the inclusion of aerobic exercise, which has been shown effective in reducing the deleterious effects in vasculature. Interest in exercise studies has increased significantly with promising results that demonstrate a future for investigation. Considering the importance of this emerging field, the aim of this mini-review is to summarize and integrate animal studies investigating physiological mechanisms of vascular dysfunction and remodeling in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and how these are influenced by chronic aerobic exercise training.     

DNA sequence variation in the promoter region of the VEGF gene impacts VEGF gene expression and maximal oxygen consumption

In its role as an endothelial cell proliferation and migration factor, vascular endothelial growth factor (VEGF) can affect peripheral circulation and therefore impact maximal oxygen consumption (Vo2 max). Because of the role of VEGF, and because variation in the VEGF gene has the ability to alter VEGF gene expression and VEGF protein level, we hypothesized that VEGF gene polymorphisms are related to VEGF gene expression in human myoblasts and Vo2 max before and after aerobic exercise training. We analyzed the effects of the VEGF -2578/-1154/-634 promoter region haplotype on VEGF gene expression by using a luciferase reporter assay in cultured human myoblasts and found that the AAG and CGC haplotypes resulted in significantly higher hypoxia-stimulated VEGF gene expression than the AGG and CGG haplotypes. Consistent with these results, we found that individuals with at least one copy of the AAG or CGC haplotype had higher Vo2 max before and after aerobic exercise training than did subjects with only the AGG and/or CGG haplotype. In conclusion, we found that VEGF -2578/-1154/-634 haplotype impacts VEGF gene expression in human myoblasts and is associated with Vo2 max. These results have potential implications for aerobic exercise training and may prove relevant in the study of pathological conditions that can be affected by angiogenesis, such as coronary artery disease and peripheral artery disease.     

A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast

Whereas the majority of disease-related mitochondrial DNA mutations exhibit significant biochemical and clinical heterogeneity, mutations within the mitochondrially encoded human cytochrome b gene (MTCYB) are almost exclusively associated with isolated complex III deficiency in muscle and a clinical presentation involving exercise intolerance. Recent studies have shown that a small number of MTCYB mutations are associated with a combined enzyme complex defect involving both complexes I and III, on account of the fact that an absence of assembled complex III results in a dramatic loss of complex I, confirming a structural dependence between these two complexes. We present the biochemical and molecular genetic studies of a patient with both muscle and brain involvement and a severe reduction in the activities of both complexes I and III in skeletal muscle due to a novel mutation in the MTCYB gene that predicts the substitution (Arg318Pro) of a highly conserved amino acid. Consistent with the dramatic biochemical defect, Western blotting and BN-PAGE experiments demonstrated loss of assembled complex I and III subunits. Biochemical studies of the equivalent amino-acid substitution (Lys319Pro) in the yeast enzyme showed a loss of enzyme activity and decrease in the steady-state level of bc1 complex in the mutant confirming pathogenicity.     

Fat to the fire: the regulation of lipid oxidation with exercise and environmental stress

Lipids are an important fuel for submaximal aerobic exercise. The ways in which lipid oxidation is regulated during locomotion is an area of active investigation. Indeed, the integration between cellular regulation of lipid metabolism and whole-body exercise performance is a fascinating but often overlooked research area. Additionally, the interaction between environmental stress, exercise, and lipid oxidation has not been sufficiently examined. There are many functional and structural steps as fatty acids are mobilized, transported, and oxidized in working muscle, which may serve either as regulatory points for responding to acute or chronic stimuli or as raw material for natural selection. At the whole-animal level, the partitioning of lipids and carbohydrates across exercise intensities is remarkably similar among mammals, which suggests that there is conservation in regulatory mechanisms. Conversely, the proportions of circulatory and intramuscular fuels differ between species and across exercise intensities. Responses to acute and chronic environmental stress likely involve the interaction of genetic and nongenetic changes in the fatty acid pathway. Determining which of these factors help regulate the fatty acid pathway and what impact they have on whole-animal lipid oxidation and performance is an important area of future research. Using an integrative approach to complete the information loop from gene to physiological function provides the most powerful mode of analysis.     

Molecular interaction networks for the analysis of human disease: Utility,limitations, and considerations

High‐throughput ‘‐omics’ data can be combined with large‐scale molecular interaction networks, for example, protein–protein interaction networks, to provide a unique framework for the investigation of human molecular biology. Interest in these integrative ‘‐omics’ methods is growing rapidly because of their potential to understand complexity and association with disease; such approaches have a focus on associations between phenotype and “network‐type.” The potential of this research is enticing, yet there remain a series of important considerations. Here, we discuss interaction data selection, data quality, the relative merits of using data from large high‐throughput studies versus a meta‐database of smaller literature‐curated studies, and possible issues of sociological or inspection bias in interaction data. Other work underway, especially international consortia to establish data formats, quality standards and address data redundancy, and the improvements these efforts are making to the field, is also evaluated. We present options for researchers intending to use large‐scale molecular interaction networks as a functional context for protein or gene expression data, including microRNAs, especially in the context of human disease.     

Linkage of hyperkalaemic periodic paralysis in Quarter horses to the horse adult skeletal muscle sodium channel gene

A genetic disease observed in certain Quarter horses is hyperkalaemic periodic paralysis (HYPP). This disease causes attacks of paralysis which can be induced by ingestion of potassium. Recent studies have shown that HYPP in humans is due to single base changes within the adult skeletal muscle sodium channel gene. A large Quarter horse pedigree segregating dominant HYPP was studied to determine if mutations of the sodium channel gene are similarly responsible for HYPP in horses. We used cross-species, PCR-mediated, cDNA cloning and sequencing of the horse adult skeletal muscle sodium channel alpha-subunit gene to identify a polymorphism, and then used this polymorphism to see if the horse sodium channel gene was genetically linked to HYPP in horses. The sodium channel gene was indeed found to be tightly linked to HYPP (LOD = 2.7, theta = 0). Our results suggest that HYPP in horses involves the same gene as the clinically similar human disease, and indicates that these are homologous disorders. The future identification of the specific sodium channel mutation causing HYPP in Quarter horses will permit the development of accurate molecular diagnostics of this condition, as has been recently shown for humans.     

Relationships between muscle mitochondrial DNA content, mitochondrial enzyme activity and oxidative capacity in man: alterations with disease

Muscle mitochondrial content is tightly regulated, and requires the expression of both nuclear and mitochondrial genes. In addition, muscle mitochondrial content is a major determinant of aerobic exercise capacity in healthy subjects. The current study was designed to test the hypothesis that in healthy humans, muscle mitochondrial DNA (mtDNA) content is correlated with citrate synthase activity (a representative nuclear-encoded mitochondrial enzyme) and aerobic exercise capacity as defined by whole-body peak oxygen consumption (VO2). Furthermore, it was postulated that these relationships might be altered with disease. Twelve healthy and five paraplegic subjects underwent exercise testing and vastus lateralis muscle biopsy sampling. An additional ten healthy subjects and eight patients with unilateral peripheral arterial disease (PAD) underwent exercise testing and gastrocnemius muscle biopsy sampling. Citrate synthase activity and mtDNA content were positively correlated in the vastus lateralis muscles from the healthy subjects. This relationship was similar in muscle from paraplegic subjects. mtDNA content was positively correlated with peak VO2 in the healthy subjects and in the paraplegic subjects in whom peak VO2 had been elicited by functional electrical stimulation of the muscle. In contrast, the PAD subjects demonstrated higher mtDNA contents than would have been predicted based on their claudication-limited peak VO2. Thus, in healthy humans there are strong relationships between muscle mtDNA content and both muscle citrate synthase activity and peak VO2. These relationships are consistent with coordinant nuclear DNA and mtDNA expression, and with mitochondrial content being a determinant of aerobic exercise capacity. The relationships seen in healthy humans are quantitatively similar in paraplegic patients, but not in patients with PAD, a disease which is associated with a metabolic myopathy. The relationships between mtDNA content, mitochondrial enzyme activities and exercise capacity provide insight into the physiologic and pathophysiologic regulation of muscle mitochondrial expression.     

Myotonic dystrophy: molecular windows on a complex etiology.

Myotonic dystrophy (DM) is the most common form of adult onset muscular dystrophy, with an incidence of approximately 1 in 8500 adults. DM is caused by an expanded number of trinucleotide repeats in the 3'-untranslated region (UTR) of a cAMP-dependent protein kinase (DM protein kinase, DMPK). Although a large number of transgenic animals have been generated with different gene constructions and knock-outs, none of them faithfully recapitulates the multisystemic and often severe phenotype seen in human patients. The transgenic data suggest that myotonic dystrophy is not caused simply by a biochemical deficiency or abnormality in the DM kinase gene product. Emerging studies suggest that two novel pathogenetic mechanisms may play a role in the disease: the expanded repeats appear to cause haploinsufficiency of a neighboring homeobox gene and also abnormal DMPK RNA appears to have a detrimental effect on RNA homeostasis. The complex, multisystemic phenotype may reflect an underlying multifaceted molecular pathophysiology: the facial dysmorphology may be due to pattern defects caused by haploinsufficiency of the homeobox gene, while the muscle disease and endocrine abnormalities may be due to both altered RNA metabolism and deficiency of the cAMP DMPK protein.     

Effect of insulin and contraction up on glucose transport in skeletal muscle

The major glucose transporter protein expressed in skeletal muscle is GLUT4. Both muscle contraction and insulin induce translocation of GLUT4 from the intracellular pool to the plasma membrane. The intracellular pathways that lead to contraction- and insulin-stimulated GLUT4 translocation seem to be different, allowing the attainment of a maximal effect when acting together. Insulin utilizes a phosphatidylinositol 3-kinase-dependent mechanism, whereas the exercise signal may be initiated by calcium release from the sarcoplasmic reticulum or from autocrine- or paracrine-mediated activation of glucose transport. During exercise skeletal muscle utilizes more glucose than when at rest. However, endurance training leads to decreased glucose utilization during sub-maximal exercise, in spite of a large increase in the total GLUT4 content associated with training. The mechanisms involved in this reduction have not been totally elucidated, but appear to cause the decrease of the amount of GLUT4 translocated to the plasma membrane by altering the exercise-induced enhancement of glucose transport capacity. On the other hand, the effect of resistance training is controversial. Recent studies, however, demonstrated the improvement in insulin sensitivity correlated with increasing muscle mass. New studies should be designed to define the molecular basis for these important adaptations to skeletal muscle. Since during exercise the muscle may utilize insulin-independent mechanisms to increase glucose uptake, the mechanisms involved should provide important knowledge to the understanding and managing peripheral insulin resistance.     

The involvement of the ubiquitin proteasome system in human skeletal muscle remodelling and atrophy

Skeletal muscle exhibits great plasticity in response to altered activity levels, ultimately resulting in tissue remodelling and substantial changes in mass. Animal research would suggest that the ubiquitin proteasome system, in particular the ubiquitin ligases MAFbx/atrogin-1 and MuRF1, are instrumental to the processes underlying these changes. This review article therefore examines the role of proteasomal-mediated protein degradation in human skeletal muscle in health and disease. Specifically, the effects of exercise, disuse and inflammatory disease states on the ubiquitin proteasome system in human skeletal muscle are examined. The article also identifies several inconsistencies between published human studies and data obtained from animal models of muscle atrophy, highlighting the need for a more comprehensive examination of the molecular events responsible for modulating muscle mass in humans.     

Skeletal muscle adaptation to exercise: a century of progress.

Skeletal muscle physiology and biochemistry is an established field with Nobel Prize-winning scientists, dating back to the 1920s. Not until the mid to late 1960s did there appear a major focus on physiological and biochemical training adaptations in skeletal muscle. The study of adaptations to exercise training reveals a wide range of integrative approaches, from the systemic to the molecular level. Advances in our understanding of training adaptations have come in waves caused by the introduction of new experimental approaches. Research has revealed that exercise can be effective at preventing and/or treating some of the most common chronic diseases of the latter half of the 20th century. Endurance-trained muscle is more effective at clearing plasma triglyceride, glucose, and free fatty acids. However, at the present time, most of the mechanisms underlying the adaptation of human skeletal muscle to exercise still remain to be discovered. Little is known about the regulatory factors (e.g., trans-acting proteins or signaling pathways) directly modulating the expression of exercise-responsive genes. Because so many potential physiological and biochemical signals change during exercise, it will be an important challenge in the next century to move beyond "correlational studies" and to identify responsible mechanisms. Skeletal muscle metabolic adaptations may prove to be a critical component to preventing diseases such as coronary heart disease, type 2 diabetes, and obesity. Therefore, training studies have had an impact on setting the stage for a potential "preventive medicine reformation" in a society needing a return to a naturally active lifestyle of our ancestors.