Neuromuscular effects related to hind limb disuse : experimental studies in the rat

University dissertation from Stockholm : Karolinska Institutet, Center for Surgical Sciences CFSS

Abstract: Disuse is known to cause skeletal muscle atrophy and a dramatic increase in bone resorption. In this work the effects of disuse were studied in rats after hind limb immobilization for 5 days, 2 weeks, 4 weeks, and 8 weeks. In addition, rats with a midshaft femur fracture were treated with adequate or undersized intramedullary pins. They were sacrificed after 3, 6, and 12 weeks. The level of nicotinic acetylcholine receptors (nAChRs) in skeletal muscle measured by quantitative receptor autoradiography increased significantly after 5 days in the SOL and after 2 weeks in the TIB muscles and continued to be high up to 8 weeks in both muscles. The level of nAChRs increased significantly 3 weeks after fractures in the TIB muscle of both treatment groups. Insulin-like growth factor-1 (IGF-I) concentration in muscle measured by radioimmunoassay (RIA), decreased significantly after 4 and 8 weeks of immobilization in the SOL and TIB muscles respectively. These results show for the first time, differences between slow and fast muscles in their response to immobilization with respect to nAChRs and IGF-I concentration. In the spinal cord IGF-I level decreased significantly on the side ipsilateral to the immobilized limb after 5 days, 2 weeks, and 4 weeks of immobilization. These data show for the first time decreased levels of IGF-I peptide in skeletal muscle and on the ipsilateral side of the lumbar spinal cord after hind limb immobilization. Despite the normal levels of IGF-I in both muscles at the early time points (5 days and 2 weeks), the decreased levels of IGF-I in the spinal cord observed at these time points suggest that the decrease might be due to an early impairment of retrograde transport from the immobilized limb muscles. The IGF-I receptor (IGF-IR) level in the lumbar spinal cord measured by quantitative receptor autoradiography increased significantly on the side ipsilateral to the immobilized limb after 4 and 8 weeks compared to controls. After the femur fractures, there was a significant increase in IGF-I receptors in the spinal cord ipsilateral to the fractured side in the group treated with the undersized nails. The enhancement of the spinal cord IGF-I receptors after hind limb immobilization may constitute part of the nervous system response to disuse. The observed changes in the spinal cord and skeletal muscle after fractures may be associated with the impaired proprioception, coordination and motor activity sometimes seen after immobilization for fractures. GH, IGF-I, and somatostatin levels in femur extracts were measured by RIA. GH levels increased significantly after 5 days, returned to control levels after 2 and 4 weeks and increased again after 8 weeks of hind limb immobilization. The IGF-I concentration was significantly increased after 2 weeks but returned to control levels at 4 weeks, and decreased significantly after 8 weeks of immobilization. The somatostatin level in the bone extracts increased significantly only after 8 weeks of hind limb immobilization. The ash density of the tibias decreased significantly in the group treated with undersized nails only and did not return to control level even after 12 weeks. These data indicate that GH and IGF-I may not only lead to bone formation but that elevated levels of these peptides can also be associated with increased net bone resorption such as after immobilization. Mechanical loading, being the most important determinant of bone density, could possibly modify the tissue effects of these factors.

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