Voluntary running reduces loss of PTEN-deficient Purkinje cells, modulates their metabolic signaling, and improves motor deficits in mice.

Abstract

Dysregulation of the PTEN-mTORC1 signaling pathway disrupts cellular metabolism and contributes to neurodevelopmental disorders, including autism spectrum disorder (ASD). In cerebellar Purkinje cells (PCs), PTEN deficiency leads to hyperactivation of mTORC1, impaired energy homeostasis, and progressive neuronal degeneration. Given that physical exercise is a potent modulator of metabolic signaling, we investigated whether voluntary running could restore metabolic balance and ameliorate cellular and behavioral deficits in a mouse model of PC-specific PTEN deficiency. Using Pten conditional knockout (cKO) mice, we evaluated the effects of voluntary running on motor coordination, metabolic signaling, neuronal morphology and preservation, and social and non-social behaviors. Behavioral analyses revealed that running significantly improved motor performance in Pten cKO mice. At the cellular level, voluntary running increased phosphorylated AMP-activated protein kinase (pAMPK) and restored mitochondrial and lysosomal content in PC dendrites from Pten cKO mice. Unexpectedly, running further enhanced mTORC1 activity in Pten cKO mice, as indicated by increased pS6R immunoreactivity, suggesting a complex interplay between anabolic and catabolic pathways. Behavioral analyses further revealed that voluntary running reduced sex-dependent differences in social and non-social behaviors observed in sedentary Pten cKO mice. Despite persistent dendritic hypertrophy and synaptic VGLUT2 alterations, running reduced PC loss and partially normalized microglial morphology and activation. Together, these findings demonstrate that voluntary running improves metabolic homeostasis and neuronal preservation in Pten cKO mice, even in the presence of sustained mTORC1 activation. Our results highlight the therapeutic potential of physical activity in modulating metabolic pathways and mitigating neurodevelopmental pathology.