Determining the role of BRCA1 in skeletal muscle regeneration

Abstract

Skeletal muscle is necessary for movement, breathing, and performance of daily activities. Acute injuries can occur to skeletal muscle, and there are several conditions and diseases that result in impairment of muscle repair (muscular dystrophies, sarcopenia, diabetes). Measurable decreases in muscle quality occur when mechanisms of muscle repair are attenuated. There is a strong correlation between muscle quality and overall mortality, thus it is important to understand the mechanisms that skeletal muscle utilizes to repair itself from injury and ensure muscle quality remains high. Satellite cells are a form of stem cell that reside in the skeletal muscle providing an innate ability to repair damaged tissue after an injury. Satellite cells repair muscle through myogenesis, which is a dynamic process that includes proliferation, differentiation, and fusion. During myogenesis, there is an unavoidable accumulation of DNA damage that must be repaired or the skeletal muscle's ability to repair the damaged tissue will be inhibited. BRCA1 is a tumor suppressor gene that maintains genomic stability by encouraging the repair of DNA damage, whose expression increases during myogenesis. Considering DNA damage occurs during myogenesis, and BRCA1 expression increases with myoblast differentiation, it suggests a critical role for BRCA1 in myogenesis. We hypothesized that BRCA1 is necessary for skeletal muscle repair. To test this hypothesis, we developed a satellite cell specific BRCA1 knockout mouse (BRCA1KOSC). An acute injury was induced to the skeletal muscle with an intramuscular injection of a BaCl2 solution in BRCA1KOSC and age matched WT littermates. The BRCA1KOSC and WT mice were put into three groups based on days post-injury: 3-day, 7-day, and 14-day. At each timepoint, EDL and TA muscles were extracted for isometric force measures and fiber size (CSA) analysis, respectively. Regardless of genotype, force production and CSA were reduced in the muscle after BaCl2-injection when compared to PBS-injection, indicating that the BaCl2 approach was successful at inducing injury. However, no effect of genotype was detected after BaCl2-injection at any timepoint, and it appeared in some cases that BRCA1KOSC mice recovered better than WT animals. In conclusion, the lack of significance between genotypes in this study led to the rejection of our initial hypothesis.