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

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Abstract

Background

Hereditary 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.

Methods

Using 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.

Results

Although 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.

Conclusions

These 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.

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Acknowledgements

We would like to thank Ruiying Cheng and Lingxue Zeng for the initial animal setup.

Funding

This study was in part supported by the U.S. NIH/NINDS R21 NS121394.

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Authors and Affiliations

  1. Department of Biomedical Engineering and Biotechnology, University of Massachusetts Lowell, Lowell, MA, 01854, USA

    Varun V. Dhorajia

  2. Department of Biomedical and Nutritional Sciences, University of Massachusetts Lowell, 3 Solomont Way, Suite 4, Lowell, MA, 01854, USA

    Jonghan Kim

  3. Department of Physical Therapy and Kinesiology, University of Massachusetts Lowell, 113 Wilder Street, Suite 393, Lowell, MA, 01854, USA

    Yuho Kim

Authors
  1. Varun V. Dhorajia
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  2. Jonghan Kim
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Corresponding authors

Correspondence to Jonghan Kim or Yuho Kim.

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Conflict of interest

Author V. Dhorajia declares that he has no conflict of interest. Author J. Kim declares that he has no conflict of interest. Author Y. Kim declares that he has no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal experiments were performed in accordance with the Guide for Care and Use of Laboratory Animals of the National Institutes of Health, and the procedure was approved by University of Massachusetts Lowell Institutional Animal Care and Use Committee (IACUC).

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Dhorajia, V.V., Kim, J. & Kim, Y. Early adaptive responses in the skeletal muscle of young mice with hereditary hemochromatosis. Mol Biol Rep 50, 3179–3187 (2023). https://doi.org/10.1007/s11033-023-08264-0

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  • DOI: https://doi.org/10.1007/s11033-023-08264-0

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