Dissection of Muscle Weight QTL Via Congenic Strains

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DESCRIPTION (provided by applicant): Dissection of Muscle Weight QTL via Congenic Strains. Although muscle mass is known to be heritable, the genetic mechanisms influencing it are incompletely understood. This lack of knowledge limits possibilities of developing pharmaceutical aids that could be used to prevent muscle loss. Genetic architecture of muscle weight in a mouse model is polygenic, with many quantitative trait loci (QTL), each accounting for a small fraction of phenotypic variance. Our goal is to initiate fine mapping of the Skmw11 locus and nominate the gene(s) influencing muscle weight. Our specific hypothesis in this proposal is that mouse chromosome (Chr) 9 harbors gene(s) affecting muscle weight. The hypothesis is based on findings from an F2 intercross between C57BL/6J and DBA/2J mouse strains that mice carrying a C57BL/6J allele within a region of 66 - 123 Mb of distal Chr 9 had significantly larger hind limb muscles than those carrying a DBA/2J allele. The specific aims are: 1) to fine map the Skmw11 locus by exploiting the availability of a set of C57BL/6.Psl1dba2 congenic strains and generate additional congenic strains to narrow down further the relevant region of Chr 9. This will be accomplished in two stages: (i) initially the weight of soleus, tibialis anterior (TA), EDL, gastrocnemius and biceps brachii (BB) muscles will be measured in congenic C57BL/6.Psl1dba2 strains and the host strain (C57BL/6J). (ii) Additional congenic strains targeting the region defined in stage (i) will be generated by backcrossing of the C57BL/6.Psl1dba2 strains and intercrossing progeny with recombinations in the region of interest. 2) Explore the mechanisms underlying variation in muscle weight by comparing host and a congenic strain for the muscular content of water, protein and glycogen. 3) Using a bioinformatics approach, search for candidate genes within the region of Chr 9 defined by congenic strain analysis with the potential to influence muscle weight.