title: Bone muscle crosstalk targets muscle regeneration pathway regulated by core circadian transcriptional repressors DEC1 and DEC2.
abstract: Deletion of proprotein convertase Mbtps1 in bone osteocytes leads to a significant postnatal increase in skeletal muscle size and contractile function, while causing only a 25% increase in stiffness in long bones. Concerns about leakiness in skeletal muscle were discounted since Cre recombinase expression does not account for our findings, and, Mbtps1 protein and mRNA is not deleted. Interestingly, the response of normal skeletal muscle to exercise and the regenerative response of skeletal muscle to the deletion of Mbtps1 in bone share some key regulatory features including a preference for slow twitch muscle fibers. In addition, transcriptional regulators PPAR, PGC-1α, LXR, and repressors DEC1 and DEC2 all occupy central positions within these two pathways. We hypothesize that the age-dependent muscle phenotype inDmp1-Cre Mbtps1 cKOmice is due to bone→muscle crosstalk. Many of the myogenic genes altered in this larger and functionally improved muscle are regulated by circadian core transcriptional repressors DEC1 and DEC2, and furthermore, display a temporal coordination withDec1andDec2expression consistent with a regulatory co-dependency. These considerations lead us to propose that Dmp1-Cre Mbtps1cKOosteocytes activate myogenesis by increased release of an activator of muscle PPAR-gamma, for example, PGE2or sphingosine-1-P, or, by diminished release of an inhibitor of LXR, for example, long-chain polyunsaturated fatty acids. We hope that further investigation of these interacting pathways in theDmp1-Cre Mbtps1 cKOmodel will lead to clinically translatable findings applicable to age-related sarcopenia and other muscle wasting syndromes.
authors.affiliation: Department of Oral and Craniofacial Sciences, School of Dentistry , Kansas City, MO, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Gorski
authors.affiliation: School of Biological Sciences University of Missouri-Kansas City , Kansas City, MO, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Price