Defects in pancreatic development and glucose metabolism in SMN-depleted mice independent of canonical spinal muscular atrophy neuromuscular pathology.
Spinal muscular atrophy (SMA) is characterized by motor neuron loss, caused by mutations or deletions in the ubiquitously expressed survival motor neuron 1 (SMN1) gene. We recently identified a novel role for Smn protein in glucose metabolism and pancreatic development in both an intermediate SMA mouse model (Smn(2B/-)) and type I SMA patients. In the present study, we sought to determine if the observed metabolic and pancreatic defects are SMA-dependent. We employed a line of heterozygous Smn-depleted mice (Smn(+/-)) that lack the hallmark SMA neuromuscular pathology and overt phenotype. At 1 month of age, pancreatic/metabolic function of Smn(+/-)mice is indistinguishable from wild type. However, when metabolically challenged with a high-fat diet, Smn(+/-)mice display abnormal localization of glucagon-producing α-cells within the pancreatic islets and increased hepatic insulin and glucagon sensitivity, through increased p-AKT and p-CREB, respectively. Further, aging results in weight gain, an increased number of insulin-producing β cells, hyperinsulinemia and increased hepatic glucagon sensitivity in Smn(+/-)mice. Our study uncovers and highlights an important function of Smn protein in pancreatic islet development and glucose metabolism, independent of canonical SMA pathology. These findings suggest that carriers of SMN1 mutations and/or deletions may be at an increased risk of developing pancreatic and glucose metabolism defects, as even small depletions in Smn protein may be a risk factor for diet- and age-dependent development of metabolic disorders.
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada The Neuroscience Institute of Montpellier (INM), Inserm UMR1051, Saint Eloi Hospital, Montpellier, France.
Melissa
M
Bowerman
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada Department of Cellular and Molecular Medicine and.
John-Paul
JP
Michalski
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Ariane
A
Beauvais
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Lyndsay M
LM
Murray
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Yves
Y
DeRepentigny
Ottawa Hospital Research Institute, Ottawa, Ontario, Canada Department of Cellular and Molecular Medicine and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada rkothary@ohri.ca.
Rashmi
R
Kothary
D000818:Animals; D008297:Male; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics*
C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein