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. 2014 Nov;13(11):3001-13.
doi: 10.1074/mcp.M113.032276. Epub 2014 Jul 3.

Quantitative proteomic analysis reveals metabolic alterations, calcium dysregulation, and increased expression of extracellular matrix proteins in laminin α2 chain-deficient muscle

Bruno Menezes de Oliveira  1 , Cintia Y Matsumura  2 , Cibely C Fontes-Oliveira  1 , Kinga I Gawlik  1 , Helena Acosta  3 , Patrik Wernhoff  1 , Madeleine Durbeej  4
Affiliations

Quantitative proteomic analysis reveals metabolic alterations, calcium dysregulation, and increased expression of extracellular matrix proteins in laminin α2 chain-deficient muscle

Bruno Menezes de Oliveira et al. Mol Cell Proteomics. 2014 Nov.

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).

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Figures

Fig. 1.
Fig. 1.
Pie charts of differentially expressed proteins in laminin α2 chain–deficient muscles grouped according to different biological processes using PANTHER classification. A, down-regulated proteins in laminin α2 chain–deficient gastrocnemius. B, up-regulated proteins in laminin α2 chain–deficient gastrocnemius. C, down-regulated proteins in laminin α2 chain–deficient diaphragm. D, up-regulated proteins in laminin α2 chain–deficient diaphragm.
Fig. 2.
Fig. 2.
Western blot analysis of selected proteins. Quantification of isocitrate dehydrogenase (IDH1), SERCA1, and calsequestrin (CASQ) by Western blot analysis of extracts of gastrocnemius muscle from wild-type and laminin α2 chain–deficient dy3K/dy3K mice. α-actinin (α-ACTN) was used as a loading control. n = 4 and p < 0.05, Mann–Whitney.
Fig. 3.
Fig. 3.
Periostin and galectin-1 are up-regulated in laminin α2 chain–deficient muscle. Cross-sections of gastrocnemius and diaphragm muscles were stained with antibodies against periostin and galectin-1. Bar, 50 μm.
See this image and copyright information in PMC

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