Stress-induced fetal programming contributes to the manifestation of Duchenne muscular dystrophy in mdx mice

Saba Gharibi; Gretel S Major; Ali Shad; Bridgette D Semple; Narelle E McGregor; Martha Blank; Gavin Abbott; Natalie A Sims; Christopher S Shaw; Aaron P Russell; Angus Lindsay

doi:10.1016/j.isci.2025.112123

Stress-induced fetal programming contributes to the manifestation of Duchenne muscular dystrophy in mdx mice

iScience. 2025 Mar 1;28(4):112123. doi: 10.1016/j.isci.2025.112123. eCollection 2025 Apr 18.

Authors

Saba Gharibi¹, Gretel S Major^{2

3}, Ali Shad^{4

5}, Bridgette D Semple^{4

5}, Narelle E McGregor⁶, Martha Blank⁶, Gavin Abbott¹, Natalie A Sims^{6

7

8}, Christopher S Shaw¹, Aaron P Russell¹, Angus Lindsay^{1

2

3

9

10}

Affiliations

¹ School of Exercise and Nutrition Sciences, Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, VIC 3216, Australia.
² School of Biological Sciences, University of Canterbury, Christchurch 8140, New Zealand.
³ Biomolecular Interaction Centre, School of Biological Sciences, University of Canterbury, Christchurch 8140, New Zealand.
⁴ Department of Neuroscience, The School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia.
⁵ Alfred Health, Prahran, VIC, Australia.
⁶ Bone Cell Biology and Disease Unit, St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
⁷ Department of Medicine, The University of Melbourne, St. Vincent's Hospital, Melbourne, VIC, Australia.
⁸ Mary Mackillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia.
⁹ Department of Medicine, University of Otago, Christchurch 8014, New Zealand.
¹⁰ Maurice Wilkins Centre for Molecular Biodiscovery, Auckland 1010, New Zealand.

Abstract

Prenatal stress predisposes offspring to neurocognitive, metabolic, and cardiovascular complications in adulthood, but the programming effects on the presentation of hereditary diseases are unknown. We investigate this in a mouse model of Duchenne muscular dystrophy (DMD), an X-linked neuromuscular disease that widely affects the central nervous system and peripheral tissues. Simulating the inheritance patterns of DMD by mating mdx-heterozygous females with wildtype males, we compare the central, autonomic, and peripheral phenotypes of healthy and DMD-affected (mdx) male offspring born from mothers that were either stressed or non-stressed during gestation. Prenatal stress predisposed mdx offspring to anxiety-like behavior and reduced bone mass but did not exacerbate stress hypersensitivity or skeletal muscle mass and function. In fact, prenatal stress increases blood pressure and may be protective against hypotension-induced mortality to stress. This demonstrates that offspring genetics influence the outcomes of fetal programming, and fetal programming influences the presentation of a hereditary disease.

Keywords: Biological sciences; Natural sciences; Neuroscience; Physiology.