title: Quantitative proteomic analysis reveals metabolic alterations, calcium dysregulation, and increased expression of extracellular matrix proteins in laminin α2 chain-deficient muscle.
abstract: Congenital muscular dystrophy with laminin α2 chain deficiency (MDC1A) is one of the most severe forms of muscular disease and is characterized by severe muscle weakness and delayed motor milestones. The genetic basis of MDC1A is well known, yet the secondary mechanisms ultimately leading to muscle degeneration and subsequent connective tissue infiltration are not fully understood. In order to obtain new insights into the molecular mechanisms underlying MDC1A, we performed a comparative proteomic analysis of affected muscles (diaphragm and gastrocnemius) from laminin α2 chain-deficient dy(3K)/dy(3K) mice, using multidimensional protein identification technology combined with tandem mass tags. Out of the approximately 700 identified proteins, 113 and 101 proteins, respectively, were differentially expressed in the diseased gastrocnemius and diaphragm muscles compared with normal muscles. A large portion of these proteins are involved in different metabolic processes, bind calcium, or are expressed in the extracellular matrix. Our findings suggest that metabolic alterations and calcium dysregulation could be novel mechanisms that underlie MDC1A and might be targets that should be explored for therapy. Also, detailed knowledge of the composition of fibrotic tissue, rich in extracellular matrix proteins, in laminin α2 chain-deficient muscle might help in the design of future anti-fibrotic treatments. All MS data have been deposited in the ProteomeXchange with identifier PXD000978 (http://proteomecentral.proteomexchange.org/dataset/PXD000978).
authors.affiliation: From the §Department of Experimental Medical Science, Unit of Muscle Biology, Lund University, BMC B12, 221 84 Lund, Sweden;
authors.forename: Bruno Menezes
authors.initials: BM
authors.lastname: de Oliveira
authors.affiliation: From the §Department of Experimental Medical Science, Unit of Muscle Biology, Lund University, BMC B12, 221 84 Lund, Sweden; ¶Departament of Functional and Structural Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas, São Paulo 13083-970, Brazil;
authors.forename: Cintia Y
authors.initials: CY
authors.lastname: Matsumura
authors.affiliation: From the §Department of Experimental Medical Science, Unit of Muscle Biology, Lund University, BMC B12, 221 84 Lund, Sweden;
authors.forename: Cibely C
authors.initials: CC
authors.lastname: Fontes-Oliveira
authors.affiliation: From the §Department of Experimental Medical Science, Unit of Muscle Biology, Lund University, BMC B12, 221 84 Lund, Sweden;
authors.forename: Kinga I
authors.initials: KI
authors.lastname: Gawlik
authors.affiliation: ‖Stem Cell Center, Lund University, BMC B12, 221 84 Lund, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Acosta
authors.affiliation: From the §Department of Experimental Medical Science, Unit of Muscle Biology, Lund University, BMC B12, 221 84 Lund, Sweden;
authors.forename: Patrik
authors.initials: P
authors.lastname: Wernhoff
authors.affiliation: From the §Department of Experimental Medical Science, Unit of Muscle Biology, Lund University, BMC B12, 221 84 Lund, Sweden; madeleine.durbeej-hjalt@med.lu.se.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Durbeej
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003964:Diaphragm / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis*; D005355:Fibrosis / Q000235:genetics / Q000473:pathology; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling; D007797:Laminin / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009137:Muscular Dystrophy, Animal; D053719:Tandem Mass Spectrometry
chemical_list: D016326:Extracellular Matrix Proteins; D007797:Laminin; C102645:laminin alpha 2; D002118:Calcium