Mild musculoskeletal and locomotor alterations in adult rats with white matter injury following prenatal ischemia.

Early brain injury including white matter damage (WMD) appears strongly correlated to perinatal hypoxia-ischemia and adverse neurological outcomes in preterm survivors. Indeed, WMD has been widely associated with subtle to major motor disturbances, sensory, behavioral and cognitive impairments in preterm infants who afterward develop cerebral palsy (CP). Prenatal ischemia (PI) has been shown to reproduce the main features of WMD observed in preterm infants. The present study was aimed at determining in adult rats the impact of PI on brain axons, musculoskeletal histology and locomotor activity. PI was induced by unilateral intrauterine artery ligation at E17 in pregnant rats. We found axonal degeneration and reactive astrogliosis in several white matter regions of adult PI rats. We found mild myopathic and secondary joint changes, including increased variability in myofiber size in several hind limb muscles, decreased myofibers numbers but increased Pax 7 cells and myofiber size in the gastrocnemius, and mild knee and ankle chondromalacia. Although treadmill locomotion appeared normal, several kinematic parameters, such as stride length, amplitude, velocity and leg joint angles were altered in adult PI rats compared to shams. Using intra- and inter-group variability of kinematic parameters, PI seemed to impair the maturation of locomotion on the treadmill. In addition, PI rats exhibited spontaneous hyperactivity in open-field test. Musculoskeletal changes appeared concomitant with mild impairments in gait and posture. Our rodent model of WMD based on PI reproduces the mild motor deficits and musculoskeletal changes observed in many preterm infants with a perinatal history of hypoxia-ischemia, and contributes towards a better understanding of the interplay between brain injury, musculoskeletal histopathology and gait disturbances encountered subsequently.

Aging enhances serum cytokine response but not task-induced grip strength declines in a rat model of work-related musculoskeletal disorders.

BACKGROUND: We previously reported early tissue injury, increased serum and tissue inflammatory cytokines and decreased grip in young rats performing a moderate demand repetitive task. The tissue cytokine response was transient, the serum response and decreased grip were still evident by 8 weeks. Thus, here, we examined their levels at 12 weeks in young rats. Since aging is known to enhance serum cytokine levels, we also examined aged rats. METHODS: Aged and young rats, 14 mo and 2.5 mo of age at onset, respectfully, were trained 15 min/day for 4 weeks, and then performed a high repetition, low force (HRLF) reaching and grasping task for 2 hours/day, for 12 weeks. Serum was assayed for 6 cytokines: IL-1alpha, IL-6, IFN-gamma, TNF-alpha, MIP2, IL-10. Grip strength was assayed, since we have previously shown an inverse correlation between grip strength and serum inflammatory cytokines. Results were compared to naïve (grip), and normal, food-restricted and trained-only controls. RESULTS: Serum cytokines were higher overall in aged than young rats, with increases in IL-1alpha, IFN-gamma and IL-6 in aged Trained and 12-week HRLF rats, compared to young Trained and HRLF rats (p < 0.05 and p < 0.001, respectively, each). IL-6 was also increased in aged 12-week HRLF versus aged normal controls (p < 0.05). Serum IFN-gamma and MIP2 levels were also increased in young 6-week HRLF rats, but no cytokines were above baseline levels in young 12-week HRLF rats. Grip strength declined in both young and aged 12-week HRLF rats, compared to naïve and normal controls (p < 0.05 each), but these declines correlated only with IL-6 levels in aged rats (r = -0.39). CONCLUSION: Aging enhanced a serum cytokine response in general, a response that was even greater with repetitive task performance. Grip strength was adversely affected by task performance in both age groups, but was apparently influenced by factors other than serum cytokine levels in young rats.