title: Muscle Signaling in Exercise Intolerance: Insights from the McArdle Mouse Model.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 1Mitochondrial and Neuromuscular Diseases Laboratory and "MITOLAB-CM," Research Institute of Hospital "12 de Octubre" ("i + 12"), Madrid, SPAIN; 2Neuromuscular and Neuropediatric Research Group, Neurosciences Department, Germans Trias i Pujol Research Institute and Campus Can Ruti, Autonomous University of Barcelona, Badalona, SPAIN; 3Department of Research and Doctorate Studies, European University, Madrid, SPAIN; 4Neuromuscular and Mitochondrial Pathology Department, Vall d'Hebron University Hospital, Research Institute (VHIR), Autonomous University of Barcelona, Barcelona, SPAIN; and 5Spanish Network for Biomedical Research in Rare Diseases (CIBERER), U723, Madrid, SPAIN.
authors.forename: Carmen
authors.initials: C
authors.lastname: Fiuza-Luces
authors.forename: Gisela
authors.initials: G
authors.lastname: Nogales-Gadea
authors.forename: Inés
authors.initials: I
authors.lastname: García-Consuegra
authors.forename: Helios
authors.initials: H
authors.lastname: Pareja-Galeano
authors.forename: Laura
authors.initials: L
authors.lastname: Rufián-Vázquez
authors.forename: Laura M
authors.initials: LM
authors.lastname: Pérez
authors.forename: Antoni L
authors.initials: AL
authors.lastname: Andreu
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arenas
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Martín
authors.forename: Tomàs
authors.initials: T
authors.lastname: Pinós
authors.forename: Alejandro
authors.initials: A
authors.lastname: Lucia
authors.forename: María
authors.initials: M
authors.lastname: Morán
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D017079:Exercise Tolerance; D055879:Gene Knock-In Techniques; D006012:Glycogen Storage Disease Type V / Q000503:physiopathology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000503:physiopathology*; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C506944:Atp2a1 protein, mouse; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases