title: Sarcolipin deletion exacerbates soleus muscle atrophy and weakness in phospholamban overexpressing mice.
abstract: Sarcolipin (SLN) and phospholamban (PLN) are two small proteins that regulate the sarco(endo)plasmic reticulum Ca2+-ATPase pumps. In a recent study, we discovered that Pln overexpression (PlnOE) in slow-twitch type I skeletal muscle fibers drastically impaired SERCA function and caused a centronuclear myopathy-like phenotype, severe muscle atrophy and weakness, and an 8 to 9-fold upregulation of SLN protein in the soleus muscles. Here, we sought to determine the physiological role of SLN upregulation, and based on its role as a SERCA inhibitor, we hypothesized that it would represent a maladaptive response that contributes to the SERCA dysfunction and the overall myopathy observed in the PlnOE mice. To this end, we crossed Sln-null (SlnKO) mice with PlnOE mice to generate a PlnOE/SlnKO mouse colony and assessed SERCA function, CNM pathology, in vitro contractility, muscle mass, calcineurin signaling, daily activity and food intake, and proteolytic enzyme activity. Our results indicate that genetic deletion of Sln did not improve SERCA function nor rescue the CNM phenotype, but did result in exacerbated muscle atrophy and weakness, due to a failure to induce type II fiber compensatory hypertrophy and a reduction in total myofiber count. Mechanistically, our findings suggest that impaired calcineurin activation and resultant decreased expression of stabilin-2, and/or impaired autophagic signaling could be involved. Future studies should examine these possibilities. In conclusion, our study demonstrates the importance of SLN upregulation in combating muscle myopathy in the PlnOE mice, and since SLN is upregulated across several myopathies, our findings may reveal SLN as a novel and universal therapeutic target.
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1.
authors.forename: Val A
authors.initials: VA
authors.lastname: Fajardo
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gamu
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mitchell
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1.
authors.forename: Darin
authors.initials: D
authors.lastname: Bloemberg
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1.
authors.forename: Eric
authors.initials: E
authors.lastname: Bombardier
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1.
authors.forename: Paige J
authors.initials: PJ
authors.lastname: Chambers
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1.
authors.forename: Catherine
authors.initials: C
authors.lastname: Bellissimo
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1.
authors.forename: Joe
authors.initials: J
authors.lastname: Quadrilatero
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1.
authors.forename: A Russell
authors.initials: AR
authors.lastname: Tupling
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D017136:Ion Transport; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism / Q000473:pathology*; D009124:Muscle Proteins / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000378:metabolism / Q000473:pathology*; D011510:Proteolipids / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000473:pathology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D017384:Sequence Deletion; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D009124:Muscle Proteins; D011510:Proteolipids; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C077258:sarcolipin