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Key Changes and Time Course of Muscle Denervation in a Rat Model
Peng Wu, MD1, Robert J. Spinner, MD1, Michael J. Yaszemski, MD, PhD2, Anthony J. Windebank, MD3 and Huan Wang, MD, PhD1,
1Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, 2 Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, 3 Department of Neurology, Mayo Clinic, Rochester, MN
Objective: This study aimed to delineate the characteristics and time course of the intrinsic changes in skeletal muscles after denervation with various intervals. Methods: Female Lewis rats with body weight of 200 ± 5 gram were subjected to sciatic nerve transection and randomized into the following 5 groups: sciatic nerve transection and denervation for 1 week (group A1, n=8), 4 weeks (group A2, n=8), 6 weeks (group A3, n=8), 8 weeks (group A4, n=8) and 12 weeks (group A5, n=8). Changes in the denervated muscles including electrophysiologic (fibrillation potential), histologic (muscle wet weight, muscle fiber types, muscle cross-sectional area, extent of fibrosis) and molecular biologic (mRNA expression levels of MRF4, myogenin, nAChR, MUSK, P21) were quantified in all rats at designated postoperative time points. Results: Fibrillation potential appeared in the medial gastrocnemius (MGS) muscle on the third day, reached peak between1 and 4 weeks and then decreased dramatically at 6 weeks postoperatively. Muscle wet weight of MGS, soleus and tibialis anterior (TA) retained approximately 78%, 36%, 30%, 24% and 18%, respectively, at 1, 4, 6, 8 and 12 weeks post-denervation. The muscle cross-sectional area (CSA) of TA and MGS gradually decreased, while the amount of connective tissues in TA and MGS gradually increased over the time course of denervation. In denervated MGS (mixed fiber type muscle) and TA (fast fiber dominant muscle), there was remarkable decrease in the proportion of type IIB fibers, whereas proportions of type I and IIA fibers increased over the time course of denervation, indicating a conversion from fast fibers to slower fibers. Changes in the soleus (slow fiber dominant muscle) suggested a conversion from slow fibers to faster ones: the proportion of type I fibers decreased while type IIA fiber proportion increased over the time course of denervation. These changes were especially obvious at 4-6 weeks postoperatively. The mRNA relative expression of myogenin, MUSK, nAChR, P21 and MRF4 in MGS increased initially, peaked at 4-6 weeks postdenervation, and then dropped to a low level. Conclusion: Following nerve injury, fibrillation potential maximal amplitude, muscle weight, muscle CSA, connective tissue content, muscle fiber composition, mRNA expression levels of myogenic factors had specific and obvious changes in the skeletal muscles. These changes were closely related to the time course of denervation, being most significant at 4-6 weeks post-denervation.
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