Early adaptive responses in the skeletal muscle of young mice with hereditary hemochromatosis

BackgroundHereditary hemochromatosis (HH) is characterized by iron overload that can cause multiple organ dysfunction primarily due to uncontrolled iron-mediated oxidative stress. Although HH leads to muscular weakness, disorder, and fatigue, the mechanism by which HH affects skeletal muscle physiology is largely unknown.MethodsUsing Hfe knockout mice (6-7 months old), a well-defined mouse model of HH, we examined iron status in the skeletal muscle, as well as other organs. As mitochondria are key organelle for muscular function, this study also explored how molecular markers for mitochondrial function and related systems are regulated in the HH skeletal muscle using western blots.ResultsAlthough iron overload was evident at the systemic level, only mild iron overload was observed in the skeletal muscle of HH. Of note, mitochondrial electron transport chain complex I was upregulated in the HH skeletal muscle, which was accompanied by enhanced autophagy. However, these molecular changes were not associated with oxidative stress, suggesting altered mitochondrial metabolism in the muscle in response to iron overload.ConclusionsThese early adaptive responses may be important for supporting mitochondrial health before fully developing skeletal muscle dysfunction in HH. More studies are needed to determine the role of autophagy in the HH-related muscle mitochondrial dysfunction.

Automated summary

In this study, using a mouse model of HH, it was found that although HH leads to systemic iron overload, only mild iron overload was observed in the skeletal muscle. Additionally, molecular markers related to mitochondrial function and autophagy were upregulated in the HH skeletal muscle, suggesting altered mitochondrial metabolism in response to iron overload. These early adaptive responses may play an important role in supporting mitochondrial health before the development of skeletal muscle dysfunction in HH.