title: SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models.
abstract: Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting secondary to repeated muscle damage and inadequate repair. Elevations in intracellular free Ca²⁺ have been implicated in disease progression, and sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 1 (SERCA1) overexpression has been shown to ameliorate the dystrophic phenotype in mdx mice. The purpose of this study was to assess the effects of SERCA1 overexpression in the more severe mdx/Utr(-/-) mouse model of DMD. Mice overexpressing SERCA1 were crossed with mdx/Utr ± mice to generate mdx/Utr(-/-)/+SERCA1 mice and compared with wild-type (WT), WT/+SERCA1, mdx/+SERCA1, and genotype controls. Mice were assessed at ∼12 wk of age for changes in Ca²⁺ handling, muscle mass, quadriceps torque, markers of muscle damage, and response to repeated eccentric contractions. SERCA1-overexpressing mice had a two- to threefold increase in maximal sarcoplasmic reticulum Ca²⁺-ATPase activity compared with WT which was associated with normalization in body mass for both mdx/+SERCA1 and mdx/Utr(-/-)/+SERCA1. Torque deficit in the quadriceps after eccentric injury was 2.7-fold greater in mdx/Utr(-/-) vs. WT mice, but only 1.5-fold greater in mdx/Utr(-/-)/+SERCA1 vs. WT mice, an attenuation of 44%. Markers of muscle damage (% centrally nucleated fibers, necrotic area, and serum creatine kinase levels) were higher in both mdx and mdx/Utr(-/-) vs. WT, and all were attenuated by overexpression of SERCA1. These data indicate that SERCA1 overexpression ameliorates functional impairments and cellular markers of damage in a more severe mouse model of DMD. These findings support targeting intracellular Ca²⁺ control as a therapeutic approach for DMD.
authors: Department of Kinesiology, School of Public Health, University of Maryland, College Park, Maryand;
authors: Davi A G
authors: DA
authors: Mázala
authors: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryand; and.
authors: Stephen J P
authors: SJP
authors: Pratt
authors: Department of Kinesiology, School of Public Health, University of Maryland, College Park, Maryand;
authors: Dapeng
authors: D
authors: Chen
authors: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Jeffery D
authors: JD
authors: Molkentin
authors: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryand; and.
authors: Richard M
authors: RM
authors: Lovering
authors: Department of Kinesiology, School of Public Health, University of Maryland, College Park, Maryand; Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, Maryand; and Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio erchin@umd.edu.
authors: Eva R
authors: ER
authors: Chin
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001696:Biomechanical Phenomena; D020013:Calcium Signaling; D052283:Creatine Kinase, MM Form / Q000097:blood; D004195:Disease Models, Animal; D005838:Genotype; D006984:Hypertrophy; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D009119:Muscle Contraction; D053580:Muscle Strength; D020388:Muscular Dystrophy, Duchenne / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009336:Necrosis; D009929:Organ Size; D010641:Phenotype; D052097:Quadriceps Muscle / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D019415:Torque; D015854:Up-Regulation; D049411:Utrophin / Q000172:deficiency / Q000235:genetics
chemical_list: D015415:Biomarkers; D049411:Utrophin; D052283:Creatine Kinase, MM Form; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: Duchenne muscular dystrophy; SERCA1; calcium; injury; mdx; mdx/Utr−/−
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