Key result
Genetic inhibition of Bcl-x short-isoform in mice led to normal development until 3 months, followed by cardiac hypertrophy, contractile dysfunction, and splenomegaly by 6 months.
Why the study?
BCL2L1 dysregulation and altered splicing variant ratios associate with pathologies, but isoform-specific loss-of-function analysis of BCL2L1 remains unexplored.
Genetic inhibition of Bcl-xS in mice leads to the development of cardiac hypertrophy and contractile dysfunction by 6 months of age, indicating its essential role in tissue homeostasis.
Bcl-xS loss induces murine cardiomyopathy; leaves open its role in human heart disease and as a therapeutic target.
BCL-2-like protein 1 (BCL2L1) is a key component of cell survival and death mechanisms. Its dysregulation and altered ratio of splicing variants associate with pathologies. However, isoform-specific loss-of-function analysis of BCL2L1 remains unexplored. Here we show the functional impact of genetically inhibiting Bcl-x short-isoform (Bcl-xS) in vivo . Bcl-xS is expressed in most tissues with predominant expression in the spleen and blood cells in mice. Bcl-xS knockout (KO) mice show no overt abnormality until 3 months of age. Thereafter, KO mice develop cardiac hypertrophy with contractile dysfunction and splenomegaly by 6 months. Cardiac fibrosis significantly increases in KO, but the frequency of apoptosis is indistinguishable despite cardiomyopathy. The Akt/mTOR and JNK/cJun signaling are upregulated in male KO heart, and the JNK/cJun is activated with increased Bax expression in KO spleen. These results suggest that Bcl-xS may be dispensable for development but is essential for maintaining the homeostasis of multiple organs.
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Keller et al. (2023) studied Cardiac hypertrophy and splenomegaly. Bcl-xS knockout vs. Wild-type mice was evaluated on Cardiac hypertrophy, contractile dysfunction, and splenomegaly. Genetic inhibition of Bcl-x short-isoform in mice led to normal development until 3 months, followed by cardiac hypertrophy, contractile dysfunction, and splenomegaly by 6 months.
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