Low-Intensity Running and High-Intensity Swimming Exercises Differentially Improve Energy Metabolism in Mice With Mild Spinal Muscular Atrophy

Abstract

Spinal Muscular Atrophy (SMA), an autosomal recessive neurodegenerative disease characterized by the loss of spinal-cord motor-neurons, is caused by mutations on Survival-of-Motor Neuron (SMN)-1 gene. The expression of SMN2, a SMN1 gene copy, partially compensates for SMN1 disruption due to exon-7 excision in 90% of transcripts subsequently explaining the strong clinical heterogeneity. Several alterations in energy metabolism, like glucose intolerance and hyperlipidemia, have been reported in SMA at both systemic and cellular level, prompting questions about the potential role of energy homeostasis and/or production involvement in disease progression. In this context, we have recently reported the tolerance of mild SMA-like mice (SmnΔ7/Δ7; huSMN2+/+) to 10 months of low-intensity running or high-intensity swimming exercise programs, respectively involving aerobic and a mix aerobic/anaerobic muscular metabolic pathways. Here, we investigated whether those exercise-induced benefits were associated with an improvement in metabolic status in mild SMA-like mice. We showed that untrained SMA-like mice exhibited a dysregulation of lipid metabolism with an enhancement of lipogenesis and adipocyte deposits when compared to control mice. Moreover, they displayed a high oxygen consumption and energy expenditure through β-oxidation increase yet for the same levels of spontaneous activity. Interestingly, both exercises significantly improved lipid metabolism and glucose homeostasis in SMA-like mice, and enhanced oxygen consumption efficiency with the maintenance of a high oxygen consumption for higher levels of spontaneous activity. Surprisingly, more significant effects were obtained with the high-intensity swimming protocol with the maintenance of high lipid oxidation. Finally, when combining electron microscopy, respiratory chain complexes expression and enzymatic activity measurements in muscle mitochondria, we found that (1) a muscle-specific decreased in enzymatic activity of respiratory chain I, II, and IV complexes for equal amount of mitochondria and complexes expression and (2) a significant decline in mitochondrial maximal oxygen consumption, were reduced by both exercise programs. Most of the beneficial effects were obtained with the high-intensity swimming protocol. Taking together, our data support the hypothesis that active physical exercise, including high-intensity protocols, induces metabolic adaptations at both systemic and cellular levels, providing further evidence for its use in association with SMN-overexpressing therapies, in the long-term care of SMA patients.

Metabolic Dysfunction in Spinal Muscular Atrophy

“…In contrast, SMA type I patients have the increased work of breathing along with feeding and swallowing problems, contributing to reduced caloric intake and increased energy expenditure [ 50 , 51 ]. From a preclinical perspective, sedentary Taiwanese (Smn ∆7/∆7 ;SMN2 +/+ ) mice, a model of severe SMA, similarly have higher energy expenditure than control animals at 12 months of age [ 56 ].…”

“…This was suggested to be compensatory to the high TG content in the Smn 2B/− livers in order to enhance clearance and restore homeostasis. Interestingly, a recent study showed that Taiwanese (Smn ∆7/∆7 ;SMN2 +/+ ) mice have a global shift in their respiratory exchange ratio, hence relying more heavily on β-oxidation [ 56 ]. The Smn 2B/− hepatic mitochondria produce more reactive oxygen species, leading to liver damage and functional deficit (protein production, hemostasis, complement, iron metabolism, insulin-like growth factor 1 (IGF1) pathway) [ 30 ].…”

“…Additionally, Smn expression in early life may be dependent on circadian rhythm in BAT, WAT, and liver tissues [ 103 ]. On the other hand, WAT appears to have increased levels of lipogenic genes in sedentary Taiwanese (Smn ∆7/∆7 ;SMN2 +/+ ) mice, which was reversed by exercise [ 56 ]. Adipokine levels remained unchanged in another study [ 30 ].…”

“…Smn 2B/− mice also show hepatic insulin resistance [ 30 ]. In the Taiwanese (Smn ∆7/∆7 ;SMN2 +/+ ) mice, plasma glucose levels were decreased as early as P4 [ 83 ], and glucose intolerance was also observed after glucose loading, which was improved by exercise [ 56 ]. In the longer-lived model, no hypoglycemia, changes in insulin sensitivity or levels were noted [ 56 ]; rather, fasting hyperglycemia was observed during the aging process.…”

In Search of a Cure: The Development of Therapeutics to Alter the Progression of Spinal Muscular Atrophy

“…However, these trophic and SMN upregulation benefits were not observed in Type II patients performing arm cycling exercises [ 313 ]. Other studies evaluating the benefits of physical exercise in mild SMA model mice found improvements in glucose homeostasis, oxygen consumption, and muscle mitochondria function [ 314 ], especially when the exercise was high intensity. Chronic exercise in these mice improved muscle fatigue, neuromuscular excitability, and increased the resistance of muscles to damage [ 315 ].…”