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 in Dmp1-Cre Mbtps1 cKO mice 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 with Dec1 and Dec2 expression consistent with a regulatory co-dependency. These considerations lead us to propose that Dmp1-Cre Mbtps1 cKO osteocytes activate myogenesis by increased release of an activator of muscle PPAR-gamma, for example, PGE₂ or 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 the Dmp1-Cre Mbtps1 cKO model will lead to clinically translatable findings applicable to age-related sarcopenia and other muscle wasting syndromes.

Figure 1

Deletion of Mbtps1 in bone (red symbols) increases muscle mass after skeletal maturity (arrow, 15–20 weeks.). Left panel, two representative litters are depicted. Right panel, two male littermates at 10 months of age. Fat content (% body wt.) is not substantially different (not shown).

Figure 2

Hypothetical pathway regulating the response of skeletal slow twitch muscle to endurance training: myogenesis, fuel usage, and myosin fiber type change.

Figure 3

Summary of proposed relationships involving SREBP1 and MBTPS1 and DEC1/DEC2 and their regulation of myogenesis in skeletal muscle.

Figure 4

Dec1 and Dec2 are subject to transcriptional regulation by environmental agents: systemic hormones, environmental conditions, and SREBP1.

Figure 5

Elevated serum insulin levels appear to be permissive for weight (lean muscle mass) gain in 12-month-old Dmp1-Cre Mbtps1 cKO mice.

Figure 6

Serum leptin is strongly correlated with total body weight for adult male Mbtps1 cKO and control mice. Red line roughly separates control data points from those for Mbtps1 cKO values. Black line represents 95% confidence regression line. r² value was determined by linear regression analysis using SigmaStat program.