Combined reduction in the expression of MCL-1 and BCL-2 reduces organismal size in mice

Abstract

The intrinsic apoptotic pathway is controlled by the BCL-2 family of proteins, which exhibit either a pro-death or pro-survival function. Gene knockout studies revealed that different pro-survival BCL-2 proteins are critical for the survival of distinct cell types, although overlapping functions amongst such proteins have also been identified. In the process of studying mice lacking single alleles of Mcl-1 (Mcl-1^+/−), Bcl-2 (Bcl-2^+/−), or both in combination (Mcl-1^+/−Bcl-2^+/−), we observed that Mcl-1^+/−Bcl-2^+/− mice weighed less when compared with their wild-type littermates as they aged. Body composition analysis demonstrated that while fat mass was similar to wild-type controls, lean mass was significantly reduced in Mcl-1^+/−, Bcl-2^+/−, and, most strikingly in Mcl-1^+/−Bcl-2^+/− mice. The weights of several tissues including the heart, tibialis anterior, and kidney were likewise reduced in Mcl-1^+/−Bcl-2^+/− mice. When lean mass and specific tissue weights were expressed relative to body weight, these differences were no longer significant, indicating that that Mcl-1^+/−Bcl-2^+/− mice, and to a lesser extent Mcl-1^+/− and Bcl-2^+/− mice, are smaller than their wild-type counterparts. Consistently, the anal-naso length was reduced in Mcl-1^+/−Bcl-2^+/− mice. While minor reductions in size were observed in female Mcl-1^+/−Bcl-2^+/− mice, these effects were most prominent in males. Notably, Mcl-1^+/−Bcl-2^+/− males had markedly smaller testes even after accounting for differences in body weight. Collectively, these data reveal that combined loss of a single allele of Mcl-1 and Bcl-2, while not overtly impairing organismal development, leads to a reduction in animal size.