Long‐term exercise‐specific neuroprotection in spinal muscular atrophy‐like mice

Abstract

Key pointsr The real impact of physical exercise parameters, i.e. intensity, type of contraction and solicited energetic metabolism, on neuroprotection in the specific context of neurodegeneration remains poorly explored.r In this study behavioural, biochemical and cellular analyses were conducted to compare the effects of two different long-term exercise protocols, high intensity swimming and low intensity running, on motor units of a type 3 spinal muscular atrophy (SMA)-like mouse model. r Our data revealed a preferential SMA-induced death of intermediate and fast motor neurons which was limited by the swimming protocol only, suggesting a close relationship between neuron-specific protection and their activation levels by specific exercise.r The exercise-induced neuroprotection was independent of SMN protein expression and associated with specific metabolic and behavioural adaptations with notably a swimming-induced reduction of muscle fatigability.r Our results provide new insight into the motor units' adaptations to different physical exercise parameters and will contribute to the design of new active physiotherapy protocols for patient care.Abstract Spinal muscular atrophy (SMA) is a group of autosomal recessive neurodegenerative diseases differing in their clinical outcome, characterized by the specific loss of spinal motor neurons, caused by insufficient level of expression of the protein survival of motor neuron (SMN). No cure is at present available for SMA. While physical exercise might represent a promising approach for alleviating SMA symptoms, the lack of data dealing with the effects of different exercise types on diseased motor units still precludes the use of active physiotherapy in SMA patients. In the present study, we have evaluated the efficiency of two long-term physical exercise paradigms, based on either high intensity swimming or low intensity running, in alleviating SMA symptoms in a mild type 3 SMA-like mouse model. We found that 10 months' physical training induced significant benefits in terms of resistance to muscle damage, energetic metabolism, muscle fatigue and motor behaviour. Both exercise types significantly enhanced motor neuron survival, independently of SMN expression, leading to the maintenance of neuromuscular junctions and skeletal muscle phenotypes, particularly in the soleus, plantaris and tibialis of trained mice. Most importantly, both exercises significantly improved neuromuscular excitability properties. Further, all these training-induced benefits were quantitatively and qualitatively related to the specific characteristics of each exercise, suggesting that the related neuroprotection is strongly

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

“…Furthermore, our data demonstrate that physiological AMPK stimulation is associated with increased SMN expression (r = 0.45, R 2 = 0.20, P < 0.05; data not shown), which extends an earlier proof-of-concept report that observed some benefits to pharmacological AMPK activation in severe SMA-like mice (Cerveró et al 2016). Previous studies present conflicting results regarding the effects of chronic exercise on SMN expression in SMA-like mice (Grondard et al 2005;Biondi et al 2015;Chali et al 2016), which are likely due, at least in part, to the disparate SMA murine models utilized, sex and age of the animals, tissues analysed, and training variables selected. Nevertheless, this important pre-clinical work reveals that significant cellular and physiological benefits, including prolonged lifespan, are likely to be gleaned by both SMN-dependent and -independent mechanisms.…”

“…; Chali et al . ), as well as by others working with SMA participants (McCartney et al . ; Madsen et al .…”

“…; Chali et al . ), which are likely due, at least in part, to the disparate SMA murine models utilized, sex and age of the animals, tissues analysed, and training variables selected. Nevertheless, this important pre‐clinical work reveals that significant cellular and physiological benefits, including prolonged lifespan, are likely to be gleaned by both SMN‐dependent and ‐independent mechanisms.…”

“…This is clearly a major weakness of using an acute exercise design. Thus, as we acknowledged recently (Ng et al 2018), future research into the area of chronic physical activity in SMA certainly requires additional studies to build on the solid foundation established by Chabonnier in the pre-clinical context (Grondard et al 2005;Biondi et al 2008;Chali et al 2016), as well as by others working with SMA participants (McCartney et al 1988;Madsen et al 2014;Lewelt et al 2015).…”

Physical exercise and glaucoma: a review on the roles of physical exercise on intraocular pressure control, ocular blood flow regulation, neuroprotection and glaucoma‐related mental health

“…Physical exercise has been investigated to promote neuronal plasticity and enhance resistance to neurodegeneration in the brain, spinal cord and cardiovascular system in both humans and experimental animals (Michelini & Stern 2009;Alvarez-Mejia et al 2015;Sandrow-Feinberg & Houle 2015;Chali et al 2016;Huttenrauch et al 2016;Li et al 2016;Otsuka et al 2016). Limited but consistent evidence of neuroprotection from exercise in animal models has been found in various retinal degenerative diseases, although the type and protocol of exercise were inconsistent and not comparable in these studies.…”