Effects of Different Continuous Aerobic Training Protocols in a Heterozygous Mouse Model of Niemann-Pick Type C Disease

Abstract

The positive effects of physical activity on cognitive functions are widely known. Aerobic training is known to promote the expression of neurotrophins, thus inducing an increase in the development and survival of neurons, as well as enhancing synaptic plasticity. Based on this evidence, in the present study, we analyze the effects of two different types of aerobic training, progressive continuous (PC) and varying continuous (VC), on synaptic and muscular plasticity in heterozygous mice carrying the genetic mutation for Niemann-Pick type C disease. We also analyze the effects on synaptic plasticity by extracellular recordings in vitro in mouse hippocampal slices, while the morphological structure of muscle tissue was studied by transmission electron microscopy. Our results show a modulation of synaptic plasticity that varies according to the type of training protocol used, and only the VC protocol administered twice a week, has a significantly positive effect on long-term potentiation. On the contrary, ultrastructural analysis of muscle tissue shows an improvement in cellular conditions in all trained mice. These results confirm the beneficial effects of exercise on quality of life, supporting the hypothesis that physical activity could represent an alternative therapeutic strategy for patients with Niemann-Pick type C disease.

Keywords: Niemann-Pick type C disease; aerobic training; mouse model; muscle plasticity; neurodegeneration; synaptic plasticity.

Figure 1

Effects of three different aerobic training protocols on physical and performance parameters. (A) The mean body weight in the control group was 18.5 ± 0.4 g at one month of life and 20.5 ± 0.4 g at four months of life. Regarding the trained mice, the mean body weight was 17.5 ± 0.5 g in the PCt group, 19.7 ± 0.3 g in the VCt group and 21.3 ± 0.7 g in the VCb group at one month of life. After training sessions, the mean body weight was 27.7 ± 1.0 g in the PCt group, 28.7 ± 0.7 g in the VCt group and 31.0 ± 0.6 g in the VCb group (**** p < 0.0001); (B) mean number of falls during the training protocol was 131.2 ± 27.7 in the PCt group, 420.0 ± 79.3 in the VCt group, and 156.0 ± 25.2 in the VCb group, with a significantly higher number of falls in the VCt group compared to the other two experimental groups (** p < 0.01).

Figure 2

Synaptic plasticity in CA1 hippocampal subfield of NPC1+/− mice. The % PS amplitude after tetanic stimulation (HFS) as a function of time is shown in NPC1+/− SEDENTARY CONTROL (black bar, n = 5), in NPC1 +/− PCt-TRAINED (pink bar, n = 5), in NPC1 +/− VCt-TRAINED (yellow bar, n = 4) and in NPC1 +/− VCb-TRAINED (green bar, n = 4) mice slices at min 1, 5, 10, 15, 20, 30, 40, 50, 60. Bars in the plot are means ± SEM of values obtained from different slices. The insert shows recordings obtained from slices of NPC1+/− SEDENTARY CONTROL (a) NPC1 +/− PCt-TRAINED (b) NPC1 +/− VCt-trained (c) and NPC1 +/− VCb-trained (d) mice. Note that a significant statistical difference was reported between the experimental groups (Min 1: CTRL vs. VCt, ** p < 0.01; PCt vs. VCt and VCt vs. VCb, * p < 0.05. Min 5: CTRL vs. VCt, * p < 0.05. Min 10: CTRL vs. VCt, ** p < 0.01; PCt vs. VCt and VCt vs. VCb, * p < 0.05. Min 15, 20 and 30: VCt vs. VCb, * p < 0.05. Min 40, 50 and 60: CTRL vs. VCb, PCt vs. VCb and VCt vs. VCb, ** p < 0.01). The first curve of each group refers to the BST and was recorded before the application of the HFS, while the other curves refer to population spikes at times 1, 20 and 60 min after the HFS.

Figure 3

Muscular plasticity adaptation following training with the different protocols. (A) The ultrastructural analysis of the muscle tissue of NPC1 +/− SEDENTARY CONTROL mice showed moderate misalignment of the sarcomeres and scarce localized vacuolizations between the myofibers. The mitochondria were well-preserved, and a slight dilation of the sarcoplasmic reticulum was visible; (B) The ultrastructural analysis of the muscle tissue of NPC1 +/− PCt-TRAINED mice displayed an improvement in cellular conditions, with poor vacuolization and perfectly aligned myofibrils. The sarcomeres were well-organized, and the mitochondria were lined up along the fibers and in a perinuclear position; (C) In the muscle tissue of NPC1 +/− VC-TRAINED mice, a well-preserved tissue organization was visible, with the correct orientation of the myofibrils. The mitochondria were well-preserved and were arranged variously between the fibers. A presence of scarce lipid droplets and a slight vacuolization was visible. Scale bar, 1 µm.