Genetic architecture of fast- and slow-twitch skeletal muscle weight in 200-day-old mice of the C57BL/6J and DBA/2J lineage

Abstract

The aim of the study was to explore the genetic architecture influencing weight of fast- and slow-twitch skeletal muscles. The weights of the slow-twitch soleus, the mixed gastrocnemius, the fast-twitch tibialis anterior (TA), and extensor digitorum longus (EDL) muscles were 11-34% greater (P < 0.001) in 200-day-old C57BL/6J (B6) than in DBA/2J (D2) mice. Male muscles were 13-28% larger than female (P < 1 x 10(-5), no strain by sex interaction). The sex-related difference in muscle weight, however, varied significantly among the 23 derivative BXD recombinant inbred (RI) strains (strain by sex interaction for soleus, P < 0.01; TA, P < 1 x 10(-4); EDL, not significant; and gastrocnemius, P < 0.001). Quantitative trait loci (QTL) affecting muscle weight were mapped in an F2 intercross of B6 and D2 mice (B6D2F2) and BXD RIs. A total of 10 autosomal, muscle-specific, but not muscle-type-specific, QTL, explaining a total of 5.4, 7.7, 22.9, and 8.6% of phenotypic variance for soleus, TA, EDL, and gastrocnemius muscles, respectively, were found across chromosomes 1 (Chr 1), 2, 3 (female-specific), 5 (two), 6, 7, 8, and 9 in B6D2F2 mice. The QTL on Chr 8 for EDL and the female-specific QTL on Chr 3 for gastrocnemius muscles were statistically significant, but the remaining QTL were at the suggestive level of statistical significance. Ten QTL on Chr 1, 2, 4, 5, 7, 8, 14, 17 (two), and 19 were identified in BXD RIs. Half of the QTL in BXD RIs had pleiotropic effects and were at the suggestive level of significance (except for the significant QTL for gastrocnemius muscle on Chr 17). The B6D2F2 nominated QTL on Chr 8 for EDL weight was validated in BXD RIs (P < 0.03). Support intervals for the QTL on Chr 1 and 5 overlapped between B6D2F2 and BXD RIs. An epistatic interaction between markers on Chr 1 and 17 affected gastrocnemius weight in BXD RIs. The interaction was not, however, validated in the B6D2F2 population. Our results indicate that the differences in muscle weight in the B6 and D2 segregating populations were the outcome of a polygenic system, with each factor contributing a small amount to the phenotypic variance and the genetic architecture affecting muscle weight was muscle specific, but not muscle-type specific, and in some instances sex specific.

Fine-mapping of muscle weight QTL in LG/J and SM/J intercrosses

“…Specificity of the Skmw22 and Skmw42 loci to soleus might be related to the distinct fiber type composition of this muscle (a mixture of type 1 and type 2A fibers) compared with the other examined muscles (predominantly a mixture of type 2A and type 2B fibers) as well as its function (soleus is a frequently used postural muscle). The effects specific to EDL (Skmw23 and Skmw24 loci) but not, for instance, to its synergist TA were also reported in the intercross between the C57BL/6J and DBA/2J strains (19,20), although the underlying mechanisms of the specificity between muscles of similar type remain unclear. Specificity of the loci affecting TA (Skmw27) and EDL (Skmw36) muscles most likely is an artifact arising from inability to discriminate between the linked loci according to the selected criteria, i.e., 3 LOD drop between the peaks, in other muscles (Fig.…”

“…This software allowed us to account for the complex relationships (e.g., sibling, half-sibling, cousins) among the AI mice by using a mixed model as described by Cheng and colleagues (7). Because of sex differences in muscle mass and also the discovery of sex-specific QTL in other studies (19,20) we explored genetic models where sex was included as either an additive or an interactive covariate.…”

“…In these studies, traits that are largely monogenic have been examined, facilitating discovery of the underlying genes. However, variation in skeletal muscle phenotypes is a polygenic trait in all species and attempts to study the polygenic architecture of muscle variation have been initiated in mice (4,20,24), pigs (26,43), and chicken (18,27,29,40). A number of quantitative trait loci (QTL) have been mapped; however, refinement of these QTL and identification of the underlying genes is a challenging problem.…”

“…The inbred strains used to make this AI were divergently selected for body size (13,22) and are thus ideally suited for this experiment. Studies in pigs (26,43), sheep (8), and mice (19,20) have demonstrated that genetic variation can exert muscle-specific effects. Therefore, we examined five different muscles in the hindlimb of mice in our populations.…”

Pleiotropic Patterns of Quantitative Trait Loci for 70 Murine Skeletal Traits

“…Studies of the genetic architecture of components of body size are becoming more and more common Leamy et al 2002;Christians et al 2003;Lionikas et al 2003;Brockmann et al 2004;Rocha et al 2004). Among components of body size, there are now many published articles on the genetic architecture of skeletal traits and aspects of skeletal morphology using quantitative trait locus (QTL) analysis (Cheverud et al 1997Leamy et al 1999;Klein et al 2001;Klingenberg et al 2001;Chase et al 2002;Li et al 2002;Shimizu et al 2002;Christians et al 2003;Volkman et al 2003;Bouxsein et al 2004;Huang et al 2004;Alam et al 2005;Carrier et al 2005;Lang et al 2005;Ishimori et al 2006;Kenney-Hunt et al 2006;Wolf et al 2006;Christians and Senger 2007;Farber and Medrano 2007;Yu et al 2007;Zhou et al 2007).…”