Σάββατο 24 Νοεμβρίου 2018

Induced‐in vivo knockdown of the Brca1 gene in skeletal muscle results in skeletal muscle weakness

Key Points Summary

Breast cancer 1, early onset gene codes for the DNA repair enzyme, breast cancer type 1 susceptibility protein (BRCA1). The gene is prone to mutations that cause a loss of protein function. BRCA1/Brca1 has recently been found to regulate several cellular pathways beyond DNA repair and is expressed in skeletal muscle. Skeletal muscle specific knockout of Brca1 in mice caused a loss of muscle quality, identifiable by reductions in muscle force production and mitochondrial respiratory capacity. Loss of muscle quality was associated with a shift in muscle phenotype and an accumulation of mitochondrial DNA (mtDNA) mutations. These results demonstrate that BRCA1 is necessary for skeletal muscle function and that increased mtDNA mutations may represent a potential underlying mechanism.

Abstract

Recent evidence suggests that the breast cancer 1, early onset gene (BRCA1) influences numerous peripheral tissues, including skeletal muscle. The purpose of this study was to determine if induced‐loss of the breast cancer type 1 susceptibility protein (Brca1) alters skeletal muscle function. We induced genetic ablation of exon 11 in the Brca1 gene specifically in skeletal muscle of adult mice to generate skeletal muscle‐specific Brca1 homozygote knockout (Brca1KOsmi) mice. Brca1KOsmi exhibited kyphosis and decreased maximal isometric force in limb muscles when compared to age‐matched wildtype (WT) mice. Brca1KOsmi skeletal muscle shifted toward an oxidative muscle fiber type and, in parallel, increased myofiber size and reduced capillary numbers. Surprisingly, myofiber bundle mitochondrial respiration was reduced while contraction‐induced lactate production was elevated in Brca1KOsmi muscle. Brca1KOsmi mice accumulated mtDNA mutations and exhibited an altered mitochondrial morphology characterized by distorted and enlarged mitochondria, and which were more susceptible to swelling. In summary, skeletal muscle‐specific loss of Brca1 leads to a myopathy and mitochondriopathy characterized by reductions in skeletal muscle quality and a consequent kyphosis. Given the substantial impact of BRCA1 mutations on cancer development risk in humans, a parallel loss of BRCA1 function in patient skeletal muscle cells would potentially result in implications for human health.

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