Muscle-restricted knockout of connexin 43 and connexin 45 accelerates and improves locomotor recovery after contusion spinal cord injury

Abstract

Traumatic spinal cord injury (SCI) results in the disruption of physiological systems below the level of the spinal lesion. Connexin hemichannels (CxHCs) are membrane-bound, non-selective pore proteins that are lost in mature myofibers 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 CxHCs 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 model was developed and tested to check 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 the body mass after complete T9 transection. There was reduced atrophy of the plantaris 15 days 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 days 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 observed in female mKO mice post-injury. The data establish a new paradigm where muscle Cx43/45 may contribute to the tissue crosstalk that determines the neuromuscular function of sub-lesional musculature after motor-incomplete SCI in a sex-dependent manner. Our novel findings should promote investigation to develop innovative treatment strategies to improve the function and quality of life for persons with SCI.