Abstract
Collagen VI is an extracellular matrix (ECM) protein playing a key role in skeletal muscles and whose deficiency leads to connective tissue diseases in humans and in animal models. However, most studies have been focused on skeletal muscle features. We performed an extensive proteomic profiling in two skeletal muscles (diaphragm and gastrocnemius) of wild-type and collagen VI null (Col6a1−/−) mice at different ages, from 6- (adult) to 12- (aged) month-old to 24 (old) month-old. While in wild-type animals the number of proteins and the level of modification occurring during aging were comparable in the two analyzed muscles, Col6a1−/− mice displayed a number of muscle-type specific variations. In particular, gastrocnemius displayed a limited number of dysregulated proteins in adult mice, while in aged muscles the modifications were more pronounced in terms of number and level. In diaphragm, the differences displayed by 6-month-old Col6a1−/− mice were more pronounced compared to wild-type mice and persisted at 12 months of age. In adult Col6a1−/− mice, the major variations were found in the enzymes belonging to the glycolytic pathway and the tricarboxylic acid (TCA) cycle, as well as in autophagy-related proteins. When compared to wild-type animals Col6a1−/− mice displayed a general metabolic rewiring which was particularly prominent the diaphragm at 6 months of age. Comparison of the proteomic features and the molecular analysis of metabolic and autophagic pathways in adult and aged Col6a1−/− diaphragm indicated that the effects of aging, culminating in lipotoxicity and autophagic impairment, were already present at 6 months of age. Conversely, the effects of aging in Col6a1−/− gastrocnemius were similar but delayed becoming apparent at 12 months of age. A similar metabolic rewiring and autophagic impairment was found in the diaphragm of 24-month-old wild-type mice, confirming that fatty acid synthase (FASN) increment and decreased microtubule-associated proteins 1A/1B light chain 3B (LC3B) lipidation are hallmarks of the aging process. Altogether these data indicate that the diaphragm of Col6a1−/− animal model can be considered as a model of early skeletal muscle aging.
Highlights
In elderly, muscle weakness and reduced muscle mass are associated with an increased risk of falls, which is in turn a primary cause of bone fracture
The same is true for sarcopenia and muscle aging, as autophagy activity is known to decline with aging and a metabolic rearrangement is a characteristic feature of aged muscles
In the present work we investigated protein alterations occurring in skeletal muscles during aging in the presence or absence of collagen VI, an extracellular matrix (ECM) protein whose mutations are causative of different muscle disorders, including Bethlem myopathy and Ullrich congenital muscular dystrophy
Summary
Muscle weakness and reduced muscle mass are associated with an increased risk of falls, which is in turn a primary cause of bone fracture. The mechanisms underlying the muscle weakness and reduced walking speed associated with loss of lean mass, defined as sarcopenia, are still poorly understood. Previous studies demonstrated that insufficient level of autophagy and dysregulation of specific metabolic pathways are linked to the onset of a dystrophic phenotype in collagen VI-related myopathies. Animal models are very valuable tools to decipher at the molecular level changes occurring during muscle aging, sarcopenia and muscle disorders. In order to carry out comparative studies between animal models and humans, a precise phenotypic characterization should be performed, accounting for both muscle development and metabolism (Capitanio et al, 2005, 2009, 2016a,b). It becomes clear that in order to translate results from human muscle into an animal model several parameters should be carefully considered, including age, muscle type, training/detraining and feeding
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