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Spiny mice are primed but fail to regenerate volumetric skeletal muscle loss injuries
Mackenzie L Davenport1,2,3,4, Amaya Fong5,6,7, Kaela N Albury5,6,7
1Department of Molecular Genetics and Microbiology, University of Florida, College of Medicine, Gainesville, FL, 32610, USA. davenport.m@ufl.edu.
Background:
In recent years, the African spiny mouse Acomys cahirinus has been shown to regenerate a remarkable array of severe internal and external injuries in the absence of a fibrotic response, including the ability to regenerate full-thickness skin excisions, ear punches, severe kidney injuries, and complete transection of the spinal cord. While skeletal muscle is highly regenerative in adult mammals, Acomys displays superior muscle regeneration properties compared with standard laboratory mice following several injuries, including serial cardiotoxin injections of skeletal muscle and volumetric muscle loss (VML) of the panniculus carnosus muscle following full-thickness excision injuries. VML is an extreme muscle injury defined as the irrecoverable ablation of muscle mass, most commonly resulting from combat injuries or surgical debridement. Barriers to the treatment of VML injury include early and prolonged inflammatory responses that promote fibrotic repair and the loss of structural and mechanical cues that promote muscle regeneration. While the regeneration of the panniculus carnosus in Acomys is impressive, its direct relevance to the study of VML in patients is less clear as this muscle has largely been lost in humans, and, while striated, is not a true skeletal muscle. We therefore sought to test the ability of Acomys to regenerate a skeletal muscle more commonly used in VML injury models.
Methods:
We performed two different VML injuries of the Acomys tibialis anterior muscle and compared the regenerative response to a standard laboratory mouse strain, Mus C57BL6/J.
Results:
Neither Acomys nor Mus recovered lost muscle mass or myofiber number within three months following VML injury, and Acomys also failed to recover force production better than Mus. In contrast, Acomys continued to express eMHC within the injured area even three months following injury, whereas Mus ceased expressing eMHC less than one-month post-injury, suggesting that Acomys muscle was primed, but failed, to regenerate.
Conclusions:
While the panniculus carnosus muscle in Acomys regenerates following VML injury in the context of full-thickness skin excision, this regenerative ability does not translate to regenerative repair of a skeletal muscle.
Insights
African spiny mice (Acomys) show remarkable regeneration but fail to regenerate skeletal muscle after volumetric muscle loss (VML) injury. Despite being primed for repair, Acomys did not recover muscle mass or function better than control mice.
Area of Science:
- Regenerative medicine
- Mammalian skeletal muscle biology
- Comparative physiology
Background:
- African spiny mouse (Acomys) exhibits exceptional regenerative capabilities for various injuries, including skin, kidney, and spinal cord.
- Acomys displays superior skeletal muscle regeneration compared to standard mice, particularly after cardiotoxin injury and volumetric muscle loss (VML) of the panniculus carnosus.
- VML injury, characterized by significant muscle mass loss, presents therapeutic challenges due to persistent inflammation and loss of regenerative cues. The panniculus carnosus in Acomys, while regenerative, is not a true skeletal muscle relevant to human VML models.
Purpose of the Study:
- To investigate the regenerative potential of Acomys in a skeletal muscle VML injury model relevant to human physiology.
- To compare the skeletal muscle regenerative response of Acomys to that of a standard laboratory mouse (Mus C57BL6/J) following VML injury.
Main Methods:
- Two distinct VML injuries were induced in the tibialis anterior muscle of Acomys.
- The regenerative outcomes in Acomys were compared with those in Mus C57BL6/J mice over a three-month period.
- Muscle mass, myofiber number, force production, and expression of embryonic myosin heavy chain (eMHC) were assessed.
Main Results:
- Neither Acomys nor Mus recovered lost muscle mass or myofiber number within three months post-VML injury.
- Acomys did not exhibit superior force production recovery compared to Mus following VML injury.
- Acomys maintained eMHC expression at three months, indicating a primed but ultimately failed regenerative state, while Mus ceased eMHC expression earlier.
Conclusions:
- The remarkable regenerative capacity of Acomys does not extend to skeletal muscle regeneration following VML injury.
- Despite evidence of a primed regenerative state (eMHC expression), Acomys failed to achieve functional recovery in skeletal muscle VML.
- These findings suggest that the mechanisms underlying Acomys's exceptional regeneration in other tissues may not directly apply to skeletal muscle VML repair.
