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Muscle Signaling in Exercise Intolerance: Insights from the McArdle Mouse Model.
- Source :
-
Medicine and science in sports and exercise [Med Sci Sports Exerc] 2016 Aug; Vol. 48 (8), pp. 1448-58. - Publication Year :
- 2016
-
Abstract
- Introduction: We recently generated a knock-in mouse model (PYGM p.R50X/p.R50X) of the McArdle disease (myophosphorylase deficiency). One mechanistic approach to unveil the molecular alterations caused by myophosphorylase deficiency, which is arguably the paradigm of "exercise intolerance," is to compare the skeletal muscle tissue of McArdle, heterozygous, and healthy (wild-type [wt]) mice.<br />Methods: We analyzed in quadriceps muscle of p.R50X/p.R50X (n = 4), p.R50X/wt (n = 6), and wt/wt mice (n = 5) (all male, 8 wk old) molecular markers of energy-sensing pathways, oxidative phosphorylation and autophagy/proteasome systems, oxidative damage, and sarcoplasmic reticulum Ca handling.<br />Results: We found a significant group effect for total adenosine monophosphate-(AMP)-activated protein kinase (tAMPK) and ratio of phosphorylated (pAMPK)/tAMPK (P = 0.012 and 0.033), with higher mean values in p.R50X/p.R50X mice versus the other two groups. The absence of a massive accumulation of ubiquitinated proteins, autophagosomes, or lysosomes in p.R50X/p.R50X mice suggested no major alterations in autophagy/proteasome systems. Citrate synthase activity was lower in p.R50X/p.R50X mice versus the other two groups (P = 0.036), but no statistical effect existed for respiratory chain complexes. We found higher levels of 4-hydroxy-2-nonenal-modified proteins in p.R50X/p.R50X and p.R50X/wt mice compared with the wt/wt group (P = 0.011). Sarco(endo)plasmic reticulum ATPase 1 levels detected at 110 kDa tended to be higher in p.R50X/p.R50X and p.R50X/wt mice compared with wt/wt animals (P = 0.076), but their enzyme activity was normal. We also found an accumulation of phosphorylated sarco(endo)plasmic reticulum ATPase 1 in p.R50X/p.R50X animals.<br />Conclusion: Myophosphorylase deficiency causes alterations in sensory energetic pathways together with some evidence of oxidative damage and alterations in Ca handling but with no major alterations in oxidative phosphorylation capacity or autophagy/ubiquitination pathways, which suggests that the muscle tissue of patients is likely to adapt overall favorably to exercise training interventions.
- Subjects :
- Animals
Disease Models, Animal
Gene Knock-In Techniques
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Oxidative Phosphorylation
Oxidative Stress
Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism
Exercise Tolerance
Glycogen Storage Disease Type V physiopathology
Muscle, Skeletal physiopathology
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1530-0315
- Volume :
- 48
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Medicine and science in sports and exercise
- Publication Type :
- Academic Journal
- Accession number :
- 27031745
- Full Text :
- https://doi.org/10.1249/MSS.0000000000000931