A systematic review investigating the effectiveness of exercise training in glycogen storage diseases

Introduction: Glycogen storage diseases (GSDs) are rare inborn errors of carbohydrate metabolism typically with skeletal muscle and liver involvement. In those with skeletal muscle involvement, the majority display symptoms of exercise intolerance which can cause profound exercise limitation and impair everyday living and quality of life (QoL). There are no curative treatments for GSDs, thus therapeutic options, such as exercise training, are aimed at improving QoL by alleviating signs and symptoms. In order to investigate the effectiveness of exercise training in adults with GSDs, we systematically reviewed the literature. Methods: In this review we conducted searches within SCOPUS and MEDLINE to identify potential papers for inclusion. These papers were independently assessed for inclusion and quality by two authors. We identified 23 studies which included aerobic training, strength training or respiratory muscle training in patients with McArdles (n = 41) and Pompe disease (n = 139). Results: In McArdle disease, aerobic exercise training improved aerobic capacity (VO2 peak) by 14–111% with further benefits to functional capacity and well-being. Meanwhile, strength training increased muscle peak power by 100–151% and reduced disease severity. In Pompe disease, a combination of aerobic and strength training improved VO2 peak by 9–10%, muscle peak power by 64%, functional capacity and well-being. Furthermore, respiratory muscle training (RMT) improved respiratory muscular strength [maximum inspiratory pressure (MIP) increased by up to 65% and maximum expiratory pressure (MEP) by up to 70%], with additional benefits shown in aerobic capacity, functional capacity and well-being. Conclusion: This adds to the growing body of evidence which suggests that supervised exercise training is safe and effective in improving aerobic capacity and muscle function in adults with McArdle or Pompe disease. However, the literature base is limited in quality and quantity with a dearth of literature regarding exercise training in other GSD subtypes

Aerobic capacity and skeletal muscle characteristics in glycogen storage disease IIIa: an observational study

Background: Individuals with glycogen storage disease IIIa (GSD IIIa) (OMIM #232400) experience muscle weakness and exercise limitation that worsen through adulthood. However, normative data for markers of physical capacity, such as strength and cardiovascular fitness, are limited. Furthermore, the impact of the disease on muscle size and quality is unstudied in weight bearing skeletal muscle, a key predictor of physical function. We aim to produce normative reference values of aerobic capacity and strength in individuals with GSD IIIa, and to investigate the role of muscle size and quality on exercise impairment. Results: Peak oxygen uptake (V̇O2peak) was lower in the individuals with GSD IIIa than predicted based on demographic data (17.0 (9.0) ml/kg/min, 53 (24)% of predicted, p = 0.001). Knee extension maximum voluntary contraction (MVC) was also substantially lower than age matched predicted values (MVC: 146 (116) Nm, 57% predicted, p = 0.045), though no difference was found in MVC relative to body mass (1.88 (2.74) Nm/kg, 61% of predicted, p = 0.263). There was a strong association between aerobic capacity and maximal leg strength (r = 0.920; p = 0.003). Substantial inter-individual variation was present, with a high physical capacity group that had normal leg strength (MVC), and relatively high V̇O2peak, and a low physical capacity that display impaired strength and substantially lower V̇O2peak. The higher physical capacity sub-group were younger, had larger Vastus Lateralis (VL) muscles, greater muscle quality, undertook more physical activity (PA), and reported higher health-related quality of life. Conclusions: V̇O2peak and knee extension strength are lower in individuals with GSD IIIa than predicted based on their demographic data. Patients with higher physical capacity have superior muscle size and structure characteristics and higher health-related quality of life, than those with lower physical capacity. This study provides normative values of these important markers of physical capacity

The protein structure initiative structural genomics knowledgebase

The Protein Structure Initiative Structural Genomics Knowledgebase (PSI SGKB, http://kb.psi-structuralgenomics.org) has been created to turn the products of the PSI structural genomics effort into knowledge that can be used by the biological research community to understand living systems and disease. This resource provides central access to structures in the Protein Data Bank (PDB), along with functional annotations, associated homology models, worldwide protein target tracking information, available protocols and the potential to obtain DNA materials for many of the targets. It also offers the ability to search all of the structural and methodological publications and the innovative technologies that were catalyzed by the PSI's high-throughput research efforts. In collaboration with the Nature Publishing Group, the PSI SGKB provides a research library, editorials about new research advances, news and an events calendar to present a broader view of structural biology and structural genomics. By making these resources freely available, the PSI SGKB serves as a bridge to connect the structural biology and the greater biomedical communitie

The protein structure initiative structural genomics knowledgebase

The Protein Structure Initiative Structural Genomics Knowledgebase (PSI SGKB, http://kb.psi-structuralgenomics.org) has been created to turn the products of the PSI structural genomics effort into knowledge that can be used by the biological research community to understand living systems and disease. This resource provides central access to structures in the Protein Data Bank (PDB), along with functional annotations, associated homology models, worldwide protein target tracking information, available protocols and the potential to obtain DNA materials for many of the targets. It also offers the ability to search all of the structural and methodological publications and the innovative technologies that were catalyzed by the PSI's high-throughput research efforts. In collaboration with the Nature Publishing Group, the PSI SGKB provides a research library, editorials about new research advances, news and an events calendar to present a broader view of structural biology and structural genomics. By making these resources freely available, the PSI SGKB serves as a bridge to connect the structural biology and the greater biomedical communities

Influence of Sequence Changes and Environment on Intrinsically Disordered Proteins

Many large-scale studies on intrinsically disordered proteins are implicitly based on the structural models deposited in the Protein Data Bank. Yet, the static nature of deposited models supplies little insight into variation of protein structure and function under diverse cellular and environmental conditions. While the computational predictability of disordered regions provides practical evidence that disorder is an intrinsic property of proteins, the robustness of disordered regions to changes in sequence or environmental conditions has not been systematically studied. We analyzed intrinsically disordered regions in the same or similar proteins crystallized independently and studied their sensitivity to changes in protein sequence and parameters of crystallographic experiments. The observed changes in the existence, position, and length of disordered regions indicate that their appearance in X-ray structures dramatically depends on changes in amino acid sequence and peculiarities of the crystallographic experiment. Our study also raises general questions regarding protein evolution and the regulation of protein structure, dynamics, and function via variations in cellular and environmental conditions

Structural Basis for Specificity of Propeptide-Enzyme Interaction in Barley C1A Cysteine Peptidases

C1A cysteine peptidases are synthesized as inactive proenzymes. Activation takes place by proteolysis cleaving off the inhibitory propeptide. The inhibitory capacity of propeptides from barley cathepsin L and B-like peptidases towards commercial and barley cathepsins has been characterized. Differences in selectivity have been found for propeptides from L-cathepsins against their cognate and non cognate enzymes. Besides, the propeptide from barley cathepsin B was not able to inhibit bovine cathepsin B. Modelling of their three-dimensional structures suggests that most propeptide inhibitory properties can be explained from the interaction between the propeptide and the mature cathepsin structures. Their potential use as biotechnological tools is discussed

Genome-wide assessment of differential roles for p300 and CBP in transcription regulation

Despite high levels of homology, transcription coactivators p300 and CREB binding protein (CBP) are both indispensable during embryogenesis. They are largely known to regulate the same genes. To identify genes preferentially regulated by p300 or CBP, we performed an extensive genome-wide survey using the ChIP-seq on cell-cycle synchronized cells. We found that 57% of the tags were within genes or proximal promoters, with an overall preference for binding to transcription start and end sites. The heterogeneous binding patterns possibly reflect the divergent roles of CBP and p300 in transcriptional regulation. Most of the 16 103 genes were bound by both CBP and p300. However, after stimulation 89 and 1944 genes were preferentially bound by CBP or p300, respectively. Target genes were found to be primarily involved in the regulation of metabolic and developmental processes, and transcription, with CBP showing a stronger preference than p300 for genes active in negative regulation of transcription. Analysis of transcription factor binding sites suggest that CBP and p300 have many partners in common, but AP-1 and Serum Response Factor (SRF) appear to be more prominent in CBP-specific sequences, whereas AP-2 and SP1 are enriched in p300-specific targets. Taken together, our findings further elucidate the distinct roles of coactivators p300 and CBP in transcriptional regulation

Comparative Genomics Reveals Two Novel RNAi Factors in Trypanosoma brucei and Provides Insight into the Core Machinery

The introduction ten years ago of RNA interference (RNAi) as a tool for molecular exploration in Trypanosoma brucei has led to a surge in our understanding of the pathogenesis and biology of this human parasite. In particular, a genome-wide RNAi screen has recently been combined with next-generation Illumina sequencing to expose catalogues of genes associated with loss of fitness in distinct developmental stages. At present, this technology is restricted to RNAi-positive protozoan parasites, which excludes T. cruzi, Leishmania major, and Plasmodium falciparum. Therefore, elucidating the mechanism of RNAi and identifying the essential components of the pathway is fundamental for improving RNAi efficiency in T. brucei and for transferring the RNAi tool to RNAi-deficient pathogens. Here we used comparative genomics of RNAi-positive and -negative trypanosomatid protozoans to identify the repertoire of factors in T. brucei. In addition to the previously characterized Argonaute 1 (AGO1) protein and the cytoplasmic and nuclear Dicers, TbDCL1 and TbDCL2, respectively, we identified the RNA Interference Factors 4 and 5 (TbRIF4 and TbRIF5). TbRIF4 is a 3′-5′ exonuclease of the DnaQ superfamily and plays a critical role in the conversion of duplex siRNAs to the single-stranded form, thus generating a TbAGO1-siRNA complex required for target-specific cleavage. TbRIF5 is essential for cytoplasmic RNAi and appears to act as a TbDCL1 cofactor. The availability of the core RNAi machinery in T. brucei provides a platform to gain mechanistic insights in this ancient eukaryote and to identify the minimal set of components required to reconstitute RNAi in RNAi-deficient parasites

Polymorphisms in the Mitochondrial Ribosome Recycling Factor EF-G2mt/MEF2 Compromise Cell Respiratory Function and Increase Atorvastatin Toxicity

Mitochondrial translation, essential for synthesis of the electron transport chain complexes in the mitochondria, is governed by nuclear encoded genes. Polymorphisms within these genes are increasingly being implicated in disease and may also trigger adverse drug reactions. Statins, a class of HMG-CoA reductase inhibitors used to treat hypercholesterolemia, are among the most widely prescribed drugs in the world. However, a significant proportion of users suffer side effects of varying severity that commonly affect skeletal muscle. The mitochondria are one of the molecular targets of statins, and these drugs have been known to uncover otherwise silent mitochondrial mutations. Based on yeast genetic studies, we identify the mitochondrial translation factor MEF2 as a mediator of atorvastatin toxicity. The human ortholog of MEF2 is the Elongation Factor Gene (EF-G) 2, which has previously been shown to play a specific role in mitochondrial ribosome recycling. Using small interfering RNA (siRNA) silencing of expression in human cell lines, we demonstrate that the EF-G2mt gene is required for cell growth on galactose medium, signifying an essential role for this gene in aerobic respiration. Furthermore, EF-G2mt silenced cell lines have increased susceptibility to cell death in the presence of atorvastatin. Using yeast as a model, conserved amino acid variants, which arise from non-synonymous single nucleotide polymorphisms (SNPs) in the EF-G2mt gene, were generated in the yeast MEF2 gene. Although these mutations do not produce an obvious growth phenotype, three mutations reveal an atorvastatin-sensitive phenotype and further analysis uncovers a decreased respiratory capacity. These findings constitute the first reported phenotype associated with SNPs in the EF-G2mt gene and implicate the human EF-G2mt gene as a pharmacogenetic candidate gene for statin toxicity in humans

The toxicity of angiotensin converting enzyme inhibitors to larvae of the disease vectors Aedes aegypti and Anopheles gambiae

The control of mosquitoes is threatened by the appearance of insecticide resistance and therefore new control chemicals are urgently required. Here we show that inhibitors of mosquito peptidyl dipeptidase, a peptidase related to mammalian angiotensin-converting enzyme (ACE), are insecticidal to larvae of the mosquitoes, Aedes aegypti and Anopheles gambiae. ACE inhibitors (captopril, fosinopril and fosinoprilat) and two peptides (trypsin-modulating oostatic factor/TMOF and a bradykinin-potentiating peptide, BPP-12b) were all inhibitors of the larval ACE activity of both mosquitoes. Two inhibitors, captopril and fosinopril (a pro-drug ester of fosinoprilat), were tested for larvicidal activity. Within 24 h captopril had killed >90% of the early instars of both species with 3rd instars showing greater resistance. Mortality was also high within 24 h of exposure of 1st, 2nd and 3rd instars of An. gambiae to fosinopril. Fosinopril was also toxic to Ae. aegypti larvae, although the 1st instars appeared to be less susceptible to this pro-drug even after 72 h exposure. Homology models of the larval An. gambiae ACE proteins (AnoACE2 and AnoACE3) reveal structural differences compared to human ACE, suggesting that structure-based drug design offers a fruitful approach to the development of selective inhibitors of mosquito ACE enzymes as novel larvicides