Mutations in the Myostatin gene leading to hypermuscularity in mammals: indications for a similar mechanism in fish?

The transforming growth factor β (TGF-β) superfamily encodes secreted factors that are important in regulating embryonic development and tissue homeostatis in adults. Myostatin (MSTN, encoded by MSTN) or 'growth and differentiation factor 8', a member of this superfamily, is a negative regulator of skeletal muscle growth and is highly conserved among animal species. In 1997, a mutation associated with the so-called double-muscling phenotype in cattle was found in the MSTN gene. During the years following the discovery of the first MSTN mutation, other mutations were found in cattle and other mammalian species, and MSTN became one of the most thoroughly studied genes in animals. The aim of this review is mainly to describe the functional mutations located in the MSTN genes of several mammalian species, leading to double muscling in these animals. Furthermore, in light of the increasing importance of fish genetics, the possibility of functional mutations in piscine MSTN with a similar effect as in mammals, and a genetic model for MSTN research in fish, will also be discussed.     

Progeny of high muscling sires have reduced muscle response to adrenaline in sheep

This study investigated the impact of variation in Australian sheep breeding values (ASBVs) for yearling eye muscle depth (YEMD) within Merino and Poll Dorset sires on intermediary metabolism of progeny. Specifically, the change in the blood concentrations of lactate, non-esterified fatty acids (NEFA) and glucose in response to administration of an exogenous dose of adrenaline was studied. The experiment used 20 Merino and Merino cross Poll Dorset mixed sex sheep. The sires were selected across a range of YEMD ASBVs. The sheep were fitted with indwelling jugular catheters and administered seven levels of adrenaline over a period of 4 days at 4 months of age (0.1, 0.2, 0.4, 0.6, 0.9, 1.2 and 1.6 μg/kg liveweight (LW)) and 16 months of age (0.1, 0.2, 0.6, 1.2, 1.8, 2.4 and 3.0 μg/kg LW). A total of 16 blood samples were collected between -30 min and 130 min relative to administration of the adrenaline challenge and were later measured for the plasma concentrations of lactate, NEFA and glucose. These data were then used to calculate the time to maximum substrate concentration, the maximum concentration and the area under curve (AUC) between 0 and 10 min, thus reflecting the substrate's response to exogenous adrenaline. Selection for muscling led to decreased muscle response due to adrenaline, as indicated by lower maximum concentrations and AUC for lactate. The muscles' response to adrenaline was more prominent at 16 months of age than at 4 months of age. Thus, animals selected for increased muscling have lower levels of glycogenolysis in situations where endogenous adrenaline levels are increased like pre-slaughter. This may minimise the risk of poor meat quality in these animals, as they will express higher muscle concentrations of glycogen at slaughter. Adipose tissue was more sensitive to adrenaline in young lambs from high YEMD sires. This shows that high muscled growing lambs utilise their adipose tissue deposits in times of stress to produce energy. This may explain the phenotypic leanness of these animals. Blood glucose levels that are indicative of liver response to adrenaline decreased with selection for muscling. This response may indicate a potential limiting of glucose that is available within animals selected for muscling, leanness and growth for brain function.     

Whole body insulin responsiveness is higher in beef steers selected for increased muscling

The aim of this experiment was to evaluate the impact of selection for greater muscling on whole body insulin responsiveness in cattle, as reflected by greater uptake of glucose in response to constant insulin infusion and greater glucose disappearance following an intravenous glucose tolerance test. This study used 18-month-old steers from an Angus herd visually assessed and selected for divergence in muscling over 15 years. Eleven high-muscled (High), 10 low-muscled (Low) and 3 high-muscled steers, which were heterozygous for a myostatin polymorphism (HighHet), were infused with insulin using the hyperinsulineamic-euglyceamic clamp technique. Insulin was constantly infused at two levels, 0.6 μIU/kg per min and 6.0 μIU/kg per min. Glucose was concurrently infused to maintain euglyceamia and the steady state glucose infusion rate (SSGIR) indicated insulin responsiveness. An intravenous glucose tolerance test was also administered at 200 mg/kg live weight. Sixteen blood samples were collected from each animal between -30 and 130 min relative to the administration of intravenous glucose, plasma glucose and insulin concentration was determined in order to analyse insulin secretion and glucose disappearance. Insulin-like growth factor-1 (IGF-1) was also measured in basal plasma samples. At the low insulin infusion rate of 0.6 mU/kg per min, the SSGIR was 73% higher for the High muscling genotype animals when compared to the Low (P<0.05). At the high insulin infusion rate of 6.0 mU/kg per min, these differences were proportionately less with the High and the HighHet genotypes having only 27% and 34% higher SSGIR (P<0.05) than the Low-muscled genotype. The High-muscled cattle also had 30% higher plasma IGF-1 concentrations compared to the Low-muscled cattle. There was no effect of muscling genotype on basal insulin or basal glucose concentrations, glucose disappearance or insulin secretion following an intravenous glucose tolerance test. The increased whole body insulin responsiveness in combination with higher IGF-1 concentrations in the High-muscled steers is likely to initiate a greater level of protein synthesis, which may partially explain the increased muscle accretion in these animals.     

Mapping of QTL on chromosome X for fat deposition, muscling and growth traits in a wild boar x Meishan F2 family using a high-density gene map

Quantitative trait loci (QTL) for fat deposition, growth and muscling traits have been previously mapped on the basis of low-density linkage maps in a wild boar × Meishan F₂ family to the chromosome X region flanked by SW2456 and SW1943 . Improved QTL resolution was possible using data for F₂ animals with a marker density of 2.7 cM distance in the SW2456 to SW1943 region, including AR , SERPINA7 and ACSL4 as candidate genes. The resolution of the QTL scan was increased substantially, as evidenced by the higher F -ratio values for all QTL. Maxima of F -ratio values for fat deposition, muscling and growth traits were 28.6, 18.2 and 16.5 respectively, and those QTL positions accounted for 7.9%, 5.0% and 4.5% of the F₂ phenotypic variance (VF₂) respectively. QTL for fatness and growth and for most muscling traits mapped near ACSL4 , with the exception of the QTL for ham traits that mapped proximally, in the vicinity of AR . An analysis performed separately for F₂ male animals showed the predominant QTL affecting fat deposition traits (up to 13.6% VF₂) near AR and two QTL for muscling traits (up to 9.9% VF₂) mapped close to ACSL4 . In the F₂ female animals, QTL affecting muscling (up to 12.1% VF₂) mapped at ACSL4 and SW2456 , and QTL for fat deposition (10% VF₂) and growth (up to 10.5% VF₂) mapped at ACSL4 .     

Inferring the recent ancestry of myostatin alleles affecting muscle mass in cattle

Double muscling is an inherited condition in cattle characterised by large increases in muscle mass. Mutations in the myostatin (MSTN) gene, responsible for double muscling, were targeted in this study to estimate the time since the most recent common ancestor (TMRCA) for Q204X (p.Gln204*), E226X (p.Glu226*), 821del11 (c.821del11), E291X (p.Glu291*), C313Y (p.Cys313Tyr) and the more phenotypically moderate F94L (p.Phe94Leu) mutation. Genetic variability was examined in eight regions upstream and downstream of the MSTN locus. The molecular distance of the homozygous region associated with each MSTN allele was used to estimate the TMRCA. Long homozygous segments were associated with the MSTN alleles (mostly > 2 Mb), compared to short segments (130 kb) for cattle wild type at the double muscling and F94L sites. Estimates of time indicated that each MSTN allele had a recent common ancestor (<400 years ago). The results from this study, and the increasing frequency of these MSTN alleles in some cattle breeds, demonstrate recent positive selection.