Breast cancer 1 gene (BRCA1) DNA
mutations impact skeletal muscle
functions. Inducible skeletal muscle specific Brca1 homozygote knockout
(Brca1KOsmi, KO) mice accumulate mitochondrial DNA (mtDNA)
mutations resulting in loss of muscle quality.1 Complementary
electrochemical andmass spectrometry analyses were utilized to rapidly
assess mtDNA or nuclear DNA (nDNA) extracted directly from mouse skeletal
muscles. Oxidative peak currents (I
p)
from DNA immobilized layer by layer (LbL) were monitored using square-wave
voltammetry (SWV) via Ru(bpy)3
2+ electrocatalysis. I
p significantly decreased (p < 0.05) for KO mtDNA compared to heterozygous KO (Het) or wild
type (WT), indicative of decreases in the guanine content. nDNA I
p significantly increased in KO compared to
WT (p < 0.05), suggesting an accumulation of damaged
nDNA. Guanine or oxidatively damaged guanine content was monitored
via appropriate m/z mass transitions
using liquid chromatography-tandem mass spectroscopy (LC-MS/MS). Guanine
in both KO mtDNA and nDNA was significantly lower, while oxidatively
damaged guanine in KO nDNA was significantly elevated versus WT. These
data demonstrate a loss of guanine content consistent with mtDNA mutation
accumulation. Oxidative damage in KO nDNA suggests that repair processes
associated with Brca1 are impacted. Overall, electrochemical and LC-MS/MS
analysis can provide chemical-level answers to biological model phenotypic
responses as a rapid and cost-effective analysis alternative to established
assays.
Breast Cancer gene 1 (BRCA1) is a large, multifunctional protein that regulates a variety of mechanisms in multiple different tissues. Our work established that Brca1 is expressed in skeletal muscle and localizes to the mitochondria and nucleus. Here, we propose BRCA1 expression is critical for the maintenance of force production and mitochondrial respiration in skeletal muscle.
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