No abstract

The murine myostatin mutation Mstn(Cmpt-dl1Abc) (Compact; C) was introduced into an inbred mouse line with extreme growth (DUHi) by marker-assisted introgression. To study the allelic effects on muscle fibre hyperplasia and hypertrophy, myonuclear proliferation, protein accretion, capillary density, and muscle fibre metabolism, samples from M. rectus femoris (RF) and M. longissimus dorsi (LD) muscles of animals wild-type (+/+), heterozygous (C/+), and homozygous (C/C) for the Mstn(Cmpt-dl1Abc) allele were examined by histological and biochemical analyses. Homozygous C/C mice exhibited lower body (-12%) but higher muscle weights (+38%) than ++ mice. Total muscle fibre number was increased (+24%), whereas fibre size was not significantly affected. Protein and DNA concentrations and DNA:protein ratios as well as specific CK activity remained unchanged for higher mass muscle implying increases in the total contents of DNA and muscle specific protein. Fibre type distribution was markedly shifted to the white glycolytic muscle fibres (+16-17% units) at the expense of red oxidative fibres. Capillary density was substantially lower in C/C than in ++ mice as seen by lower number of capillaries per fibre (-35%) and larger fibre area per capillary (+77%). However, the Mstn(Cmpt-dl1Abc) allele was partially recessive in heterozygous C/+ mice for both fibre type frequencies and capillary density. The results show that hypermuscularity caused by mutations in the myostatin gene results from muscle fibre hyperplasia rather than hypertrophy, and from balanced increases in myonuclear proliferation and protein accretion. However, capillary supply is adversely affected and muscle metabolism shifted towards glycolysis, which could have negative consequences for physical fitness.

Myostatin is a negative regulator of muscle growth and mutations in its gene lead to muscular hypertrophy and reduced fat. In cattle, this is seen in 'double muscled' breeds. We have used marker-assisted introgression to introduce a murine myostatin mutation, MstnCmpt-dl1Abc [Compact (C)], into an inbred line of mice (DUHi) that had been selected on body weight and had exceptional growth. Compared with homozygous wild-type mice, homozygous (C/C) mice of this line were approximately 4-5 % lighter, had approximately 7-8 % shorter tails, substantially increased muscle weights (e.g. quadriceps muscle in males was 59 % heavier) and an increased 'dressing percentage' (approximately 49 % vs 39 %), an indicator of overall muscularity. The weights of several organs (e.g. liver, kidney, heart and digestive tract) were significantly reduced, by 12-20 %. Myostatin deficiency also resulted in drastic reductions of total body fat and of various fat depots, total body fat proportion falling from approximately 17.5 % in wild-type animals of both sexes to 9.5 % and 11.6% in homozygous (C/C) females and males, respectively. Males with a deficiency in myostatin had higher gains in muscle traits than females. Additionally, there was a strong distortion of the segregation ratio on the DUHi background. Of 838 genotyped pups from inter se matings 29 %, 63 % and 8 % were homozygous wild type (+/+), heterozygous (C/+) and homozygous (C/C), respectively, showing that MstnCmpt-dl1Abc has lower fitness on this background. This line, when congenic, will be a useful resource in gene expression studies and for finding modifying genes.

Abstract. The mouse outbred stock Fzt:DU has been bred in the Research Institute for the Biology of Farm Animals Dummerstorf, Germany for about 30 years. This paper describes the history and the development of some traits in this stock over 128 generations. It has been used as base population for several lines long-term selected for fertility, growth, fitness and behaviour and has been bred with an average number of 200 breeding pairs per generation using a rotational mating scheme. A simulation study was employed to investigate the effect of genetic random drift on the allele frequencies. The change of the drift variance, the probabilities for allele losses and the development of the effective population size over generations are represented. The effective population size was relatively high, compared to other mouse experiments worldwide, however the genetic variability of the Fzt:DU population is substantially reduced due the high number of generations of isolated reproduction. After 120 generations, the variance effective population size is reduced to approximately 3 animals.

From our data, we conclude that the physiological basis of genetically fixed higher endurance-running performance in DUhTP marathon mouse is related to increased hepatic gluconeogenesis and lipogenesis. Expression of sirtuin 1 as well as of gluconeogenic and lipogenic key enzymes may be related to peroxisome proliferator-activated receptor delta. Metabolic adaptations presented in our study represent inborn features of superior endurance-running performance.