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ORIGINAL RESEARCH article
Front. Physiol.
Sec. Striated Muscle Physiology
Volume 15 - 2024 |
doi: 10.3389/fphys.2024.1486691
Muscle-restricted knockout of connexin43 and connexin45 accelerates and improves locomotor recovery after contusion spinal cord injury
Provisionally accepted
Carlos A. Toro
1,2*
Rita De Gasperi
1,2
Katherine Vaneslow
3
Lauren Harlow
2
Kaitlin Johnson
2
Abdurrahman Aslan
1,2
William A. Bauman
2
Christopher P. Cardozo
1,2
Zachary A. Graham
3*- 1 Icahn School of Medicine at Mount Sinai, New York, United States
- 2 Spinal Cord Damage Research Center, James J. Peters VA Medical Center, Bronx, New York, United States
- 3 Florida Institute for Human and Machine Cognition, Florida, Illinois, United States
Traumatic spinal cord injury (SCI) results in disruption of physiological systems below the level of spinal lesion. Connexin hemichannels (CxHC) are membrane-bound non-selective pore proteins that are lost with maturity but reappear de novo on the sarcolemma after peripheral denervation, chronic SCI, diabetes, and severe systemic stress such as sepsis. Cx43 and Cx45 have been implicated as the major CxHC present in diseased muscle and muscle-restricted knockout of these genes reduces muscle atrophy after denervation, likely by reducing excess calcium influx with resultant inflammasome activation. A muscle-restricted Cx43/45 conditional knockout (mKO) mouse was developed and tested whether it would improve outcomes following either a complete spinal cord transection at the level of thoracic vertebrae-9 (T9) or a motor-incomplete T9 impact-contusion SCI. mKO had no effect on body mass after complete T9 transection. There was reduced atrophy of the plantaris 15 d post-SCI that was not associated with molecular markers of inflammation, hypertrophic/atrophic protein signaling or protein and mRNA expression related to mitochondrial integrity and function. mKO mice had faster and greater locomotor recovery across 28 d after a motor-incomplete contusion SCI with no differences in spared white matter; male mKO mice generally had greater muscle mass than genotype controls post-injury, but muscle sparing was not in female mKO mice observed post-injury. The data establish a new paradigm wherein muscle Cx43/45 may contribute to the tissue crosstalk that determines neuromuscular function of sublesional musculature after motor-incomplete SCI in a manner that is dependent on gender. Our novel findings should stimulate investigation to develop innovative treatment strategies to improve function and quality of life for persons with SCI.
Keywords: sci, Cx43 (connexin 43), Skeletal Muscle-Restricted KO, cx45, Contusion spinal cord injury, transection SCI, Recovery of Function
Received: 26 Aug 2024; Accepted: 07 Oct 2024.
Copyright: © 2024 Toro, De Gasperi, Vaneslow, Harlow, Johnson, Aslan, Bauman, Cardozo and Graham. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Carlos A. Toro, Icahn School of Medicine at Mount Sinai, New York, United States
Zachary A. Graham, Florida Institute for Human and Machine Cognition, Florida, Illinois, United States
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