Intracellular Signaling in Skeletal Muscle is Dysregulated in a Pre‐Clinical Model of Spinal Muscular Atrophy
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abstract
Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality and the second most prevalent autosomal recessive disorder. SMA, which is caused by mutations in the survival motor neuron (SMN) gene, is a neuromuscular disorder (NMD) without a cure. Stimulation of key molecules that regulate skeletal muscle phenotype can be therapeutic in chronic diseases such as obesity and type 2 diabetes, as well as in some NMD contexts. Indeed, many characteristics of AMP‐activated protein kinase (AMPK), p38 mitogen‐activated protein kinase, and peroxisome proliferator‐activated receptor γ coactivator‐1α (PGC‐1α) serve to favorably maintain and remodel skeletal muscle biology. However, the expression and function of these phenotype‐bending molecules have yet to be studied in a SMA. Thus, the purpose of this study was to examine these signaling pathways in the skeletal muscle of a pre‐clinical model of SMA. Quadriceps (QUAD) and gastrocnemius (GAST) muscles were obtained from wild‐type (WT) animals (n = 7), as well as from mice harboring an Smn2B/− mutation (SMA; n = 7) at postnatal day (p) 21. These SMA mice recapitulate the neuromuscular abnormalities characteristic of the human disorder, and display a disease onset at ~ p10 and demonstrate a mean life expectancy of ~28 days. Western blot analyses were employed to examine SMN, AMPK, p38, and PGC‐1α protein levels in mixed QUAD and GAST muscle homogenates. Skeletal muscle mass was ~60–70% lower (p < 0.05) in SMA mice relative to their age‐matched, WT littermate counterparts. SMN protein content was ~85% lower (p < 0.05) in the muscles from SMA mice, as compared to the WT group. Total AMPK and p38 protein content were similar between genotypes. However, phosphorylated AMPK and p38 levels were ~50% lower (p < 0.05) in the SMA mice. PGC‐1α expression, a downstream target of AMPK and p38, was significantly reduced (−60%) in the muscle of SMA mice relative to the WT group. This decrement in PGC‐1α expression was also observed using immunofluorescence techniques. Collectively, these data indicate that SMA is associated with a reduction in molecules that are important for maintaining healthy skeletal muscle, as well as for remodeling skeletal muscle phenotype. In a separate cohort of animals (n = 1), at p17 SMA and WT mice ran on a motorized treadmill (3 m/min) until the inability to continue exercise was determined. During the run, WT mice were exposed to incremental increases of 2 m/min every 5 minutes. SMA mice ran ~80% less (p < 0.05) than their WT counterparts. While exercise appeared to increase AMPK and p38 phosphorylation in both genotypes, the induction tended to be greater in the SMA animals. In summary, this study enhances our knowledge of skeletal muscle disease biology in SMA. Furthermore, preliminary data suggest that exercise may enhance signaling for SMN induction in skeletal muscle.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada and Canada Research Chairs
