Molecular, Histological, and Functional Changes in Acta1-MCM;FLExDUX4/+ Mice.

Area of Science:

• Biomedical Research
• Muscle Physiology
• Genetics

Background:

• Facioscapulohumeral dystrophy (FSHD) is a progressive muscular disorder primarily caused by the DUX4 gene.
• The ACTA1-MCM/FLExDUX4 mouse model is widely used to study DUX4-induced muscular dystrophy.
• Investigating molecular and histological changes in DUX4 models is crucial for understanding disease progression and therapeutic targets.

Purpose of the Study:

• To investigate molecular and histological changes in tibialis anterior and quadriceps muscles of the ACTA1-MCM/FLExDUX4 mouse model at various time points.
• To identify potential markers for assessing therapeutic efficacy in FSHD mouse models.
• To develop and validate a comprehensive functional force test for evaluating DUX4-induced muscle dysfunction.

Main Methods:

• Molecular and histological analysis of muscle tissues from ACTA1-MCM/FLExDUX4 mice.
• Assessment of DUX4-pathway gene expression.
• Development and application of a novel force-velocity-endurance testing model on DUX4-expressing mice without tamoxifen induction.

Main Results:

• Confirmed progressive muscular dystrophy in the DUX4 mouse model.
• Identified potential biases associated with tamoxifen injections and DUX4-pathway gene composite scores.
• The novel force-velocity-endurance test revealed DUX4 expression leads to reduced initial muscle force but maintained power and endurance capacity.

Conclusions:

• The ACTA1-MCM/FLExDUX4 mouse model exhibits progressive muscular dystrophy, but tamoxifen use requires careful consideration.
• DUX4 expression impacts previously unsuspected muscle properties, affecting force production.
• The developed force-velocity-endurance model is a valuable tool for evaluating DUX4-related muscle deficits and has potential for human clinical application in FSHD.