title: Overexpression of phospholamban in slow-twitch skeletal muscle is associated with depressed contractile function and muscle remodeling.
abstract: The relative amount of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) and its crucial inhibitor phospholamban (PLN) are closely regulated and play a pivotal role in maintaining muscle function. The functional importance of PLN has been intensively investigated in cardiac muscle. However, little is known about the role of PLN in the slow-twitch skeletal muscle, which expresses a significantly lower level of PLN but a similar level of SERCA2a compared with cardiac muscle. Thus, to define the physiological significance of PLN in slow-twitch skeletal muscle, we generated transgenic mice with PLN-specific overexpression in soleus, which is largely composed of slow-muscle fibers. The PLN protein levels and the PLN/SERCA2a ratio in transgenic soleus were comparable with those in cardiac muscle. Assessment of isometric-twitch contractions indicated that PLN overexpression was associated with depressed rates of contraction and relaxation, which were not linked to reduced SERCA2a abundance, although the levels of other key Ca2+-handling proteins, including ryanodine receptor, FKBP12, and L-type Ca2+ channel, were significantly decreased. However, isoproterenol stimulation reversed the inhibitory effects of PLN on the transgenic soleus twitch kinetics. Furthermore, the PLN-overexpressing soleus had smaller muscle size, mass, and cross-sectional area compared with wild-types. Interestingly, the percentage of slow fibers was increased in PLN-overexpressing soleus. Taken together, these findings indicate that increased PLN expression in slow-twitch skeletal muscle is associated with impaired contractile function and muscle remodeling.
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267-0575, USA.
authors.forename: Qiujing
authors.initials: Q
authors.lastname: Song
authors.forename: Karen B
authors.initials: KB
authors.lastname: Young
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Chu
authors.forename: James
authors.initials: J
authors.lastname: Gulick
authors.forename: Michael
authors.initials: M
authors.lastname: Gerst
authors.forename: Ingrid L
authors.initials: IL
authors.lastname: Grupp
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007537:Isometric Contraction / Q000187:drug effects / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development* / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban