RT Journal Article
SR Electronic
T1 The beneficial effect of chronic muscular exercise on muscle fragility is increased by <em>Prox1</em> gene transfer in dystrophic <em>mdx</em> muscle
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.22.453435
DO 10.1101/2021.07.22.453435
A1 Alexandra Monceau
A1 Clément Delacroix
A1 Mégane Lemaitre
A1 Gaelle Revet
A1 Denis Furling
A1 Onnik Agbulut
A1 Arnaud Klein
A1 Arnaud Ferry
YR 2021
UL http://biorxiv.org/content/early/2021/07/22/2021.07.22.453435.abstract
AB Purpose Greater muscle fragility is thought to cause the exhaustion of the muscle stem cells during successive degeneration/repair cycles, leading to muscle wasting and weakness in Duchenne muscular dystrophy. Chronic voluntary exercise can partially reduce the susceptibility to contraction induced-muscle injury, i.e., muscle fragility, as shown by a reduced immediate maximal force drop following lengthening contractions, in the dystrophic mdx mice. Here, we studied the effect of Prospero-related homeobox factor 1 gene (Prox1) transfer (overexpression) on fragility in chronically exercised mdx mice, because Prox1 promotes slower type fibres in healthy mice and slower fibres are less fragile in mdx muscle.Methods mdx mice received or not Prox1 transfer into the tibialis anterior muscle and performed voluntary running into a wheel during 1 month. We also performed Prox1 transfer in sedentary mdx mice. In situ maximal force production of the muscle in response to nerve stimulation was assessed before, during and after 10 lengthening contractions. Molecular and cellular parameters were also evaluated.Results Interestingly, Prox1 transfer reduced the force drop following lengthening contractions in exercised mdx mice (p &lt; 0.05 to 0.01), but not in sedentary mdx mice. It also increased the muscle expression of Myh7 (p &lt; 0.001), MHC-2x (p &lt; 0.01) and Trpc1 (p &lt; 0.01), whereas it reduced that one of Myh4 (p &lt; 0.001) and MHC-2b (p &lt; 0.01) in exercised mdx mice. Moreover, Prox1 transfer decreased the maximal force (p &lt; 0.01) before lengthening contraction in exercised mdx mice (p &lt; 0.01), and reduced muscle weight (p &lt; 0.0001) despite increased Mstn expression (p &lt; 0.001).Conclusion Our results indicate that the beneficial effect of Prox1 transfer on muscle fragility is only observed in chronically exercised mdx mice. Thus, Prox1 transfer combined to chronic exercise have the potential to substantially slow the progression of the dystrophic disease in the long term.Competing Interest StatementThe authors have declared no competing interest.