Exercise-induced signaling in skeletal muscle of spinal muscular atrophy mice

Abstract

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality and second most prevalent autosomal recessive disorder. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene resulting in the deficiency of the crucial survival motor neuron protein (SMN). Prescribed physical activity is an emerging therapy for this disorder, however the cellular and molecular mechanisms of exercise in SMA have yet to be fully elucidated. Examining the exercise biology of SMA may prompt the discovery of novel and effective therapeutic avenues for this pathology. Hence, we sought to determine the effects of a single bout of physical activity on intracellular signaling cascades and SMN expression in the skeletal muscle of SMA-like animals. AMP-activated protein kinase (AMPK) and p38 mitogen-activated kinase (p38) expression and activity were unchanged at pre-, early-, and late-symptomatic stages of Smn2B/- mice, which suggests that important molecular machinery for driving exercise adaptations were preserved. We then subjected Smn2B/- animals to an acute, endurance-based exercise protocol and collected skeletal muscle tissue immediately after or 3 hours post-exercise. Physical activity elicited significant activation of the AMPK-p38-peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) axis in Smn2B/- animals, which confirmed the preservation of canonical exercise-induced signaling in the SMA-like condition. Exercise also elicited alterations in the activation of protein kinase B (AKT), extracellular signal-regulated kinase (ERK), and ETS-like gene 1 (ELK). Collectively, these exercise-induced changes in the AMPK-p38-PGC-1α and AKT/ERK/ELK cascades occurred coincident with enhanced SMN expression. Lastly, acute exercise resulted in the normalization of autophagic signaling, indicating that physical activity may serve a novel role in correcting the aberrant autophagy program in SMA. In summary, this study expands our knowledge of the molecular mechanisms of exercise biology in SMA and identifies the AMPK-p38-PGC-1α signaling axis as a potential regulator of SMN expression.