Changes in Muscle Cell Metabolism and Mechanotransduction Are Associated with Myopathic Phenotype in a Mouse Model of Collagen VI Deficiency

Sara De Palma,Roman Polishchuk,Paolo Bernardi,Michele Vasso,Cecilia Gelfi,Paola Braghetta,Paolo Bonaldo,Daniele Capitanio,Roberta Leone,Paolo Grumati

doi:10.1371/journal.pone.0056716

Abstract

This study identifies metabolic and protein phenotypic alterations in gastrocnemius, tibialis anterior and diaphragm muscles of Col6a1−/− mice, a model of human collagen VI myopathies. All three muscles of Col6a1−/− mice show some common changes in proteins involved in metabolism, resulting in decreased glycolysis and in changes of the TCA cycle fluxes. These changes lead to a different fate of α-ketoglutarate, with production of anabolic substrates in gastrocnemius and tibialis anterior, and with lipotoxicity in diaphragm. The metabolic changes are associated with changes of proteins involved in mechanotransduction at the myotendineous junction/costameric/sarcomeric level (TN-C, FAK, ROCK1, troponin I fast) and in energy metabolism (aldolase, enolase 3, triose phosphate isomerase, creatine kinase, adenylate kinase 1, parvalbumin, IDH1 and FASN). Together, these change may explain Ca2+ deregulation, impaired force development, increased muscle-relaxation-time and fiber damage found in the mouse model as well as in patients. The severity of these changes differs in the three muscles (gastrocnemius<tibialis anterior<diaphragm) and correlates to the mass-to-tendon (myotendineous junction) ratio and to muscle morphology.

Highlights

Collagen VI is an extracellular matrix (ECM) protein that provides a structural link between ECM and the cell basement membranes [1]
Mutations in any of the three genes coding for collagen VI (COL6A1, COL6A2, COL6A3) result in defective ECM composition and cause a wide clinical spectrum of collagen VI myopathies including Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) [8,9,10,11] and myosclerosis myopathy [12]
sirtuin 1 (SIRT1) did not change, in the tibialis anterior it was slightly increased, while in diaphragm it was significantly increased (Fig. 5, panel E). These results suggest that the decrease in Gapdh and the decrease of pyruvate dehydrogenase lipoamide beta (Pdhb) may modulate the NAD+/NADH ratio, resulting in SIRT1 overexpression

Summary

Introduction

Collagen VI is an extracellular matrix (ECM) protein that provides a structural link between ECM and the cell basement membranes [1]. The ECM-basement membrane complex acts as a sensor that transfers the contractile force from the sarcomere to cells and to the tendon [2] translating extracellular mechanical stimuli into intracellular biochemical signals (mechanotransduction) [3,4,5,6]. Collagen VI myopathies are characterized by muscle weakness and contractures, associated with variable degrees of joint hyperlaxity. UCMD, the most severe form of collagen VI disorders, is characterized by early onset and proximal joint contractures associated with striking distal hyperlaxity. A milder form of human collagen VI myopathy is BM, characterized by early contractures of finger flexors, wrist, elbows and ankles. Respiratory failure and distal hyperlaxity are usually absent or are milder than in UCMD, the latter may occur only in very young children with BM [8,17,18,19]

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