Sex-Specific Control of Muscle Mass: Elevated IGFBP Proteolysis and Reductions of IGF-1 Levels Are Associated with Substantial Loss of Carcass Weight in Male DU6PxIGFBP-2 Transgenic Mice.

Daniela Ohde,Antonia Noce,Christina Walz,Julia Brenmoehl,Michael Walz,Andreas Hoeflich,Martina Langhammer

doi:10.3390/cells9102174

Abstract

In farmed animals, carcass weight represents an important economic trait. Since we had demonstrated that IGFBP-2 represents a potent inhibitor of muscle accretion in inbred mice, we wanted to quantify the inhibitory effects of IGFBP-2 under conditions of elevated protein mass in growth selected non-inbred mice (DU6P). Therefore, we crossed male DU6P mice with female IGFBP-2 transgenic mice. Male IGFBP-2 transgenic offspring (DU6P/IGFBP-2) were characterized by more than 20% reductions of carcass mass compared to male non-transgenic littermates. The carcass mass in males was also significantly lower (p < 0.001) than in transgenic female DU6P/IGFBP-2 mice, which showed a reduction of less than 10% (p < 0.05) compared to non-transgenic female DU6P/IGFBP-2 mice. Although transgene expression was elevated in the muscle of both sexes (p < 0.001), serum levels were normal in female, but significantly reduced in male transgenic DU6P/IGFBP-2 mice (p < 0.001). In this group, also IGFBP-3 and IGFBP-4 were significantly reduced in the circulation (p < 0.01). Particularly in male transgenic mice, we were able to identify proteolytic activity against recombinant IGFBP-2 included in diluted serum. IGFBP-proteolysis in males correlated with massive reductions of IGF-1 in serum samples and the presence of elevated levels of IGFBP-2 fragments. From our data, we conclude that elevated tissue expression of IGFBP-2 is an essential effector of muscle accretion and may block more than 20% of carcass mass. However, in the circulation, intact IGFBP-2 contained no reliable biomarker content. Notably, for the estimation of breeding values in meat-producing animal species, monitoring of IGFBP-2 expression in muscle appears to be supported by the present study in a model system.

Highlights

IGFBP-2 was identified as a candidate gene for negative growth regulation under conditions of growth selection [1]
In C57BL/6 inbred mice, we have demonstrated that IGFBP-2 is a potent inhibitor of carcass weight In C57BL/6 inbred mice, wewe have demonstrated that IGFBP-2
IGFBP-2 blocks is a potent inhibitor of carcass and muscle accretion

Summary

Introduction

IGFBP-2 was identified as a candidate gene for negative growth regulation under conditions of growth selection [1]. Forced expression of IGFBP-2 in transgenic mice confirmed IGFBP-2 as an inhibitor of somatic growth but further identified muscle as a sensitive tissue for the negative effects of IGFBP-2 [2,3]. In the same muscle from male IGFBP-2 transgenic mice, the weight reductions were further characterized by reduced cross-sectional area, whereas the number of myofibers was not affected by the genotype [4]. This effect was not identified in female IGFBP-2 transgenic mice

Methods

Results

Conclusion