Effect of diet on the survival and phenotype of a mouse model for spinal muscular atrophy

Abstract

Proximal spinal muscular atrophy (SMA) is a leading genetic cause of infant death. Patients with SMA lose alpha-motor neurons in the ventral horn of the spinal cord which leads to skeletal muscle weakness and atrophy. SMA is the result of reduction in Survival Motor Neuron (SMN) expression. Transgenic mouse models of SMA have been generated and are extremely useful in understanding the mechanisms of motor neuron degeneration in SMA and in developing new therapeutic candidates for SMA patients. Several research groups have reported varying average lifespans of SMNDelta7 SMA mice (SMN2(+/+);SMNDelta7(+/+);mSmn(-/-)), the most commonly used mouse model for preclinical therapeutic candidate testing. One environmental factor that varied between research groups was maternal diet. In this study, we compared the effects of two different commercially available rodent chows (PicoLab20 Mouse diet and Harlan-Teklad 22/5 diet) on the survival and motor phenotype of the SMNDelta7 mouse model of SMA. Specifically, the PicoLab20 diet significantly extends the average lifespan of the SMNDelta7 SMA mice by approximately 25% and improved the motor phenotype as compared to the Harlan diet. These findings indicate that maternal diet alone can have considerable impact on the SMA phenotype.

Copyright 2009 Elsevier Inc. All rights reserved.

Figures

Fig 1

Effect of diet on survival and motor phenotype of SMNΔ7 SMA mice. (A). Kaplan-Meier survival plots of SMNΔ7 SMA mice from dams transitioned from the Harlan-Teklad 22/5 diet to the PicoLab20 Mouse diet. (B). Kaplan-Meier analysis of the onset of body mass loss an indicator of the late stages of disease in SMNΔ7 SMA mice from dams fed the PicoLab20 Mouse diet or the Harlan-Teklad 22/5 diet. (C). Body mass curves for SMNΔ7 SMA mice as well as WT littermates from dams fed either the PicoLab 20 Mouse or the Harlan-Teklad 22/5 diets. Key: *, p<0.05 when comparing SMNΔ7 SMA to WT mice. (D) Righting reflex latencies for SMNΔ7 SMA mice as well as WT littermates at PND07 and PND11 from dams fed either the PicoLab20 Mouse diet of the Harlan-Teklad 22/5 diet. (E) Vectorial movement latencies for SMNΔ7 SMA mice as well as WT littermates at PND07, PND11 and PND14 from dams fed either the PicoLab20 Mouse diet of the Harlan-Teklad 22/5 diet. (F) Spontaneous locomotor activity—as measured by the number of grids crossed in 1 minute—for SMNΔ7 SMA mice as well as WT littermates at PND07, PND11 and PND14 from dams fed either the PicoLab20 Mouse diet of the Harlan-Teklad 22/5 diet. (G) The number of 90° pivots in 1 minute for SMNΔ7 SMA mice as well as WT littermates at PND07, PND11 and PND14 from dams fed either the PicoLab20 Mouse diet of the Harlan-Teklad 22/5 diet. Key: *, p<0.05 when comparing SMNΔ7 SMA to WT mice; #, p<0.05 when comparing PicoLab20-fed to Harlan-Teklad 22/5-fed mice. (H). Effect of diet on motor neuron numbers in the lumbar spinal cords of SMNΔ7 SMA mice at PND11. Key: *, p<0.05 when comparing SMNΔ7 SMA to WT mice.

Fig. 2

Effect of diet on blood metabolite levels in SMNΔ7 SMA mice. (A). Blood glucose levels for SMNΔ7 SMA mice as well as WT littermates at PND12 from dams fed either the PicoLab20 Mouse diet of the Harlan-Teklad 22/5 diet. (B). Blood β-hydroxybutyrate levels for SMNΔ7 SMA mice as well as WT littermates at PND12 from dams fed either the PicoLab20 Mouse diet of the Harlan-Teklad 22/5 diet. (C). Blood free fatty acids levels for SMNΔ7 SMA mice as well as WT littermates at PND12 from dams fed either the PicoLab20 Mouse diet of the Harlan-Teklad 22/5 diet.

Fig. 3

Effect of diet on the expression of SMN and plastin-3 proteins in the spinal cords of SMNΔ7 SMA mice at PND08. The β-actin band shows that equivalent amounts of protein were loaded in each lane.

Fig. 4

Kaplan-Meier survival plots of SMNΔ7 SMA mice from dams transitioned from the PicoLab20 Mouse diet to the Harlan-Teklad 22/5 diet for 1 (A), 2 (B) and 3 (C) generations.