Calmodulin Kinase-Mediated Phosphorylation of Phospholamban in Skeletal Muscle Sarcoplasmic Reticulum. A Critical Reappraisal of the State of the Problem at the Light of New Findings with Human Normal and Diseased Muscle

The Ca-transport system of the sarcoplasmic reticulum (SR) of mammalian hind-limb slow-twitch muscles has unique regulatory features, that have long been attributed to the special differentiating influence from the particular frequency and pattern of discharge of the innervating α motorneurons in the anterior horns of the spinal cord. This review summarizes the molecular mechanisms underlying such specific effects, focusing on phosphorylation of phospholamban (PLB) and of SR Ca-ATPase by calmodulin kinase II (CaM K II). Regarding specifically the hypothesis according to which the neural control over the expression of fiber-type specific gene products in skeletal muscle SR encompasses the expression of PLB gene, there is divergent evidence, when the problem is examined in a wide range of mammalian species, from small rodent species to the human species. The discrepancy is underlined by observations, that the protein level of expression of PLB is virtually zero in rat slow-twitch muscle, and that it increases with animal body size; and with a consequent lack of correlation with the total amount of slow-twitch muscle CaATPase isoform found to be relatively immutable across different mammalian species. The experimental evidence appearing to be in conflict with the paradigma, is particularly striking in the case of human skeletal muscle having a mixed fiber composition. Most interestingly, transitions of Ca-ATPase isoforms in human skeletal muscle fibers, under pathohological conditions leading to the appearance of intermediate fibers, were found not to be accompanied by down-regulation either of PLB or of CaM K II, suggesting that in such muscle expression of PLB and of the fast-twitch Ca-ATPase isoform may be not mutually exclusive, or not in the absolute sense predicted by theory. The outstanding property that seems to link human skeletal and cardiac SR together, is the high PLB/CaATPase ratio. A common property with rabbit slow-twitch muscle SR appears to be the presence of a highly active, PLB-dedicated form of CaM K II. The postulated, complex interplay beween intracellular Ca fluxes and the activity state of CaM K II, while adding interesting new facets to the regulatory features of SR Ca-transport, inevitably invites to a number of questions, regarding the exact correlation between such mechanisms and the E-C characteristics and twitch properties of the muscle, depending also on the animal species.