Mechanisms of exercise‐induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy‐like mice

KEY POINTS: Spinal muscular atrophy (SMA) is a health- and life-limiting neuromuscular disorder caused by a deficiency in survival motor neuron (SMN) protein. While historically considered a motor neuron disease, current understanding of SMA emphasizes its systemic nature, which requires addressing affected peripheral tissues such as skeletal muscle in particular. Chronic physical activity is beneficial for SMA patients, but the cellular and molecular mechanisms of exercise biology are largely undefined in SMA. After a single bout of exercise, canonical responses such as skeletal muscle AMP-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (p38) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) activation were preserved in SMA-like Smn^2B/- animals. Furthermore, molecules involved in SMN transcription were also altered following physical activity. Collectively, these changes were coincident with an increase in full-length SMN transcription and corrective SMN pre-mRNA splicing. This study advances understanding of the exercise biology of SMA and highlights the AMPK-p38-PGC-1α axis as a potential regulator of SMN expression in muscle. ABSTRACT: Chronic physical activity is safe and effective in spinal muscular atrophy (SMA) patients, but the underlying cellular events that drive physiological adaptations are undefined. We examined the effects of a single bout of exercise on molecular mechanisms associated with adaptive remodelling in the skeletal muscle of Smn^2B/- SMA-like mice. Skeletal muscles were collected from healthy Smn^2B/+ mice and Smn^2B/- littermates at pre- (postnatal day (P) 9), early- (P13) and late- (P21) symptomatic stages to characterize SMA disease progression. Muscles were also collected from Smn^2B/- animals exercised to fatigue on a motorized treadmill. Intracellular signalling and gene expression were examined using western blotting, confocal immunofluorescence microscopy, real-time quantitative PCR and endpoint PCR assays. Basal skeletal muscle AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (p38) expression and activity were not affected by SMA-like conditions. Canonical exercise responses such as AMPK, p38 and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) activation were observed following a bout of exercise in Smn^2B/- animals. Furthermore, molecules involved in survival motor neuron (SMN) transcription, including protein kinase B (AKT) and extracellular signal-regulated kinases (ERK)/ETS-like gene 1 (ELK1), were altered following physical activity. Acute exercise was also able to mitigate aberrant proteolytic signalling in the skeletal muscle of Smn^2B/- mice. Collectively, these changes were coincident with an exercise-evoked increase in full-length SMN mRNA expression. This study advances our understanding of the exercise biology of SMA and highlights the AMPK-p38-PGC-1α axis as a potential regulator of SMN expression alongside AKT and ERK/ELK1 signalling.