Abstract
While the long-term physiological adaptation of the neuromuscular system to changed functional demands is usually reflected by unilateral skeletal muscle transitions, the progressive degeneration of distinct motor neuron populations is often associated with more complex changes in the abundance and/or isoform expression pattern of contractile proteins and metabolic enzymes. In order to evaluate these intricate effects of primary motor neuronopathy on the skeletal muscle proteome, label-free MS was employed to study global alterations in the WR (wobbler) mouse model of progressive neurodegeneration. In motor neuron disease, fibre-type specification and the metabolic weighting of bioenergetic pathways appear to be strongly influenced by both a differing degree of a subtype-specific vulnerability of neuromuscular synapses and compensatory mechanisms of fibre-type shifting. Proteomic profiling confirmed this pathobiochemical complexity of disease-induced changes and showed distinct alterations in 72 protein species, including a variety of fibre-type-specific isoforms of contractile proteins, metabolic enzymes, metabolite transporters and ion-regulatory proteins, as well as changes in molecular chaperones and various structural proteins. Increases in slow myosin light chains and the troponin complex and a decrease in fast MBP (myosin-binding protein) probably reflect the initial preferential loss of the fast type of neuromuscular synapses in motor neuron disease.
Highlights
The continuum of mammalian skeletal muscles is characterized by distinct fibre-type-specific differences in physiological, biochemical and cellular properties [1,2,3] and this is reflected on the molecular level by highly complex and differential protein expression patterns [4,5,6]
The proteomic analysis verified the complexity of neurodegeneration-related changes in skeletal muscle from the WR mouse model of amyotrophic lateral sclerosis (ALS) and identified novel changes in proteins involved in fibre contraction, energy metabolism, metabolite transportation, ion handling, structural integrity and the cellular stress response
Primary antibodies were purchased from Abcam [ab55559 to myosin-binding protein (MBP) C; ab97708 to troponin TnT; ab48003 to myosin light-chain 2 (MLC2); ab8592 to desmin; ab41803 to annexin; ab26300 to lamin; ab6588 to collagen; ab13496 to αB-crystallin; ab85366 to carbonic anhydrase CA3; ab43176 to ATP-synthase; ab36329 to isocitrate dehydrogenase; and ab28172 to prohibitin] and Sigma Chemical Company (L-9393 to laminin)
Summary
c 2014 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC-BY) (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.
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