Skeletal muscle possesses a remarkable capacity to regenerate when injured, but when confronted with major traumatic injury resulting in volumetric muscle loss (VML), the regenerative process consistently fails. The loss of muscle tissue and function from VML injury has prompted development of a suite of therapeutic approaches but these strategies have proceeded without a comprehensive understanding of the molecular landscape that drives the injury response. Herein, we administered a VML injury in an established rodent model and monitored the evolution of the healing phenomenology over multiple time points using muscle function testing, histology, and expression profiling by RNA sequencing. The injury response was then compared to a regenerative medicine treatment using orthotopic transplantation of autologous minced muscle grafts (~1 mm3 tissue fragments). A chronic inflammatory and fibrotic response was observed at all time points following VML. These results suggest that the pathological response to VML injury during the acute stage of the healing response overwhelms endogenous and therapeutic regenerative processes. Overall, the data presented delineate key molecular characteristics of the pathobiological response to VML injury that are critical effectors of effective regenerative treatment paradigms.
Bibliographical noteFunding Information:
The authors gratefully acknowledge Mrs. Monica Jalomo, Mrs. Shayna Levine, and Ms. Monica Farley for technical support during these experiments, Tom Sheehan for assistance with artwork, Tamara Mason, Tyler Miselis, Fontina Kelley, and the Broad Institute Genomics Platform for sequencing and technical assistance, and Darrell O. Ricke for insightful discussions. This material is based on work supported under Air Force Contract No. FA8721-05-C-0002 and/or FA8702-15-D-0001. This work was also supported by the Neuromusculoskeletal Injuries Research Award, Clinical and Rehabilitative Medicine Research Program, United States Army Medical Research, and Materiel Command (MR140099). Opinions, interpretations, recommendations, and conclusions are those of the authors and are not necessarily endorsed by the United States Government. Any opinions, findings, conclusions, or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the U.S. Air Force GSM3150345, GSM3150346, GSM3150347, GSM3150348, GSM3150349, GSM3150350, GSM3150351, GSM3150352, GSM3150353, GSM3150354, GSM3150355, GSM3150356, GSM3150357, GSM3150358, GSM3150359, GSM3150360, GSM3150361, GSM3150362, GSM3150363, GSM3150364, GSM3150365, GSM3150366, GSM3150367, GSM3150368, GSM3150369, GSM3150370, GSM3150371, GSM3150372, GSM3150373, GSM3150374, GSM3150375, GSM3150376, GSM3150377, GSM3150378, GSM3150379, GSM3150380, GSM3150381, GSM3150382, GSM3150383, GSM3150384, GSM3150385, GSM3150386, GSM3150387, GSM3150388, GSM3150389, GSM3150390, GSM3150391, GSM3150392, GSM3150393, GSM3150394, GSM3150395, GSM3150396, GSM3150397, GSM3150398, GSM3150399, GSM3150400, GSM3150401, GSM3150402, GSM3150403, GSM3150404, GSM3150405, GSM3150406, GSM3150407, GSM3150408, GSM3150409, GSM3150410, GSM3150411, GSM3150412, GSM3150413, GSM3150414, GSM3150415, GSM3150416, GSM3150417, GSM3150418, GSM3150419, GSM3150420, GSM3150421, GSM3150422, GSM3150423, GSM3150424, GSM3150425, GSM3150426, GSM3150427, GSM3150428, GSM3150429, GSM3150430, GSM3150431, GSM3150432, GSM3150433, GSM3150434, GSM3150435, GSM3150436, GSM3150437, GSM3150438, GSM3150439, GSM3150440, GSM3150441, GSM3150442, GSM3150443, GSM3150444, GSM3150445, GSM3150446, GSM3150447, GSM3150448, GSM3150449, GSM3150450, GSM3150451, GSM3150452, GSM3150453, GSM3150454, GSM3150455, GSM3150456, GSM3150457, GSM3150458, GSM3150459, GSM3150460, GSM3150461, GSM3150462, GSM3150463, GSM3150464, GSM3150465, GSM3150466, GSM3150467, GSM3150468, GSM3150469, GSM3150470, GSM3150471, GSM3150472, GSM3150473, GSM3150474, GSM3150475, GSM3150476, GSM3150477, GSM3150478, GSM3150479, GSM3150480, GSM3150481, GSM3150482.
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