Cytotoxic Aggregation and Amyloid Formation by the Myostatin Precursor Protein

Myostatin, a negative regulator of muscle growth, has been implicated in sporadic inclusion body myositis (sIBM). sIBM is the most common age-related muscle-wastage disease with a pathogenesis similar to that of amyloid disorders such as Alzheimer's and Parkinson's diseases. Myostatin precursor protein (MstnPP) has been shown to associate with large molecular weight filamentous inclusions containing the Alzheimer's amyloid beta peptide in sIBM tissue, and MstnPP is upregulated following ER stress. The mechanism for how MstnPP contributes to disease pathogenesis is unknown. Here, we show for the first time that MstnPP is capable of forming amyloid fibrils in vitro. When MstnPP-containing Escherichia coli inclusion bodies are refolded and purified, a proportion of MstnPP spontaneously misfolds into amyloid-like aggregates as characterised by electron microscopy and binding of the amyloid-specific dye thioflavin T. When subjected to a slightly acidic pH and elevated temperature, the aggregates form straight and unbranched amyloid fibrils 15 nm in diameter and also exhibit higher order amyloid structures. Circular dichroism spectroscopy reveals that the amyloid fibrils are dominated by β-sheet and that their formation occurs via a conformational change that occurs at a physiologically relevant temperature. Importantly, MstnPP aggregates and protofibrils have a negative effect on the viability of myoblasts. These novel results show that the myostatin precursor protein is capable of forming amyloid structures in vitro with implications for a role in sIBM pathogenesis

Nutrient dense, low-cost foods can improve the affordability and quality of the new zealand diet—a substitution modeling study

The high prevalence of non-communicable disease in New Zealand (NZ) is driven in part by unhealthy diet selections, with food costs contributing to an increased risk for vulnerable population groups. This study aimed to: (i) identify the nutrient density-to-cost ratio of NZ foods; (ii) model the impact of substituting foods with a lower nutrient density-to-cost ratio with those with a higher nutrient density-to-cost ratio on diet quality and affordability in representative NZ population samples for low and medium socioeconomic status (SES) households by ethnicity; and (iii) evaluate food processing level. Foods were categorized, coded for processing level and discretionary status, analyzed for nutrient density and cost, and ranked by nutrient density-to-cost ratio. The top quartile of nutrient dense, low-cost foods were 56% unprocessed (vegetables, fruit, porridge, pasta, rice, nuts/seeds), 31% ultra-processed (vegetable dishes, fortified bread, breakfast cereals unfortified <15 g sugars/100 g and fortified 15–30 g sugars/100 g), 6% processed (fruit juice), and 6% culinary processed (oils). Using substitution modeling, diet quality improved by 59% and 71% for adults and children, respectively, and affordability increased by 20–24%, depending on ethnicity and SES. The NZ diet can be made healthier and more affordable when nutritious, low-cost foods are selected. Processing levels in the healthier, modeled diet suggest that some non-discretionary ultra-processed foods may provide a valuable source of low-cost nutrition for food insecure populations

The C313Y Piedmontese mutation decreases myostatin covalent dimerisation and stability

<p>Abstract</p> <p>Background</p> <p>Myostatin is a key negative regulator of muscle growth and development, whose activity has important implications for the treatment of muscle wastage disorders. Piedmontese cattle display a double-muscled phenotype associated with the expression of C313Y mutant myostatin. <it>In vivo</it>, C313Y myostatin is proteolytically processed, exported and circulated extracellularly but fails to correctly regulate muscle growth. The C313Y mutation removes the C313-containing disulphide bond, an integral part of the characteristic TGF-β cystine-knot structural motif.</p> <p>Results</p> <p>Here we present <it>in vitro </it>analysis of the structure and stability of the C313Y myostatin protein that reveals significantly decreased covalent dimerisation for C313Y myostatin accompanied by a loss of structural stability compared to wild type. The C313Y myostatin growth factor, processed from full length precursor protein, fails to inhibit C2C12 myoblast proliferation in contrast to wild type myostatin. Although structural modeling shows the substitution of tyrosine causes structural perturbation, biochemical analysis of additional disulphide mutants, C313A and C374A, indicates that an intact cystine-knot motif is a major determinant in myostatin growth factor stability and covalent dimerisation.</p> <p>Conclusions</p> <p>This research shows that the cystine-knot structure is important for myostatin dimerisation and stability, and that disruption of this structural motif perturbs myostatin signaling.</p

Priority nutrients to address malnutrition and diet-related diseases in Australia and New Zealand

BackgroundThe double burden of malnutrition and diet-related disease has been attributed to diets high in ultra-processed and discretionary foods, with increased sugars, saturated fats, and sodium, and insufficient dietary fibre. There is a limited understanding of the role of other macronutrients and micronutrients.ObjectiveDetermine the highest priority nutrients to address both malnutrition and diet-related disease in Australia and New Zealand, for each demographic group and the total population.MethodsA novel four-step methodological approach was undertaken to identify: 1. Demographic (age-sex) groups; 2. Health priorities; 3. Potential nutrients based on inadequacy, increased requirements, and health priority association; and 4. Priority nutrients. Nutrient intake data was obtained from the most recent Australian and New Zealand nutrition surveys. Health priorities were based on national statistical data and expert consultation. High-level scientific literature (systematic reviews) was scoped for associations with health priorities and the suitability of recommended intakes. A quantitative scoring matrix was developed and used to determine the highest priority nutrients, with scoring over three domains: extent of inadequacy; consensus for increased requirements; and degree of association with health priorities.ResultsNutritional inadequacies were common, with 22 of 31 essential nutrients consumed below recommended levels. Nine priority nutrients were identified across the demographic groups, with each demographic group characterised by a specific subset of these. Six nutrients were highest priority within the total population: vitamin D, calcium, omega-3 fatty acids, magnesium, folate, dietary fibre.ConclusionThe extent of nutritional inadequacies in Australia and New Zealand is high, both within each demographic group and the entire population, relative to both recommended intakes and key health outcomes. The methodology can be applied to other countries and globally. Findings make a significant contribution to understanding the nutrients to prioritise in future-proofing the health of the Australian and New Zealand populations. Guidelines and policies can target priority nutrients to address the malnutrition and diet-related disease double burden

Dietary thiols in exercise: oxidative stress defence, exercise performance, and adaptation

Endurance athletes are susceptible to cellular damage initiated by excessive levels of aerobic exercise-produced reactive oxygen species (ROS). Whilst ROS can contribute to the onset of fatigue, there is increasing evidence that they play a crucial role in exercise adaptations. The use of antioxidant supplements such as vitamin C and E in athletes is common; however, their ability to enhance performance and facilitate recovery is controversial, with many studies suggesting a blunting of training adaptations with supplementation. The up-regulation of endogenous antioxidant systems brought about by exercise training allows for greater tolerance to subsequent ROS, thus, athletes may benefit from increasing these systems through dietary thiol donors. Recent work has shown supplementation with a cysteine donor (N-acetylcysteine; NAC) improves antioxidant capacity by augmenting glutathione levels and reducing markers of oxidative stress, as well as ergogenic potential through association with delayed fatigue in numerous experimental models. However, the use of this, and other thiol donors may have adverse physiological effects. A recent discovery for the use of a thiol donor food source, keratin, to potentially enhance endogenous antioxidants may have important implications for endurance athletes hoping to enhance performance and recovery without blunting training adaptations.fals