Skeletal Muscle, but not Cardiovascular Function, Is Altered in a Mouse Model of Autosomal Recessive Hypophosphatemic Rickets

Abstract

Autosomal recessive hypophosphatemic rickets (ARHR) is a heritable disorder characterized by hypophosphatemia, osteomalacia, and poor bone development. ARHR results from inactivating mutations in the DMP1 gene with the human phenotype being recapitulated in the Dmp1 null mouse model which displays elevated plasma fibroblast growth factor 23. While the bone phenotype has been well-characterized, it is not known what effects ARHR may also have on skeletal, cardiac, or vascular smooth muscle function, which is critical to understand in order to treat patients suffering from this condition. In this study, the extensor digitorum longus (EDL-fast-twitch muscle), soleus (SOL–slow-twitch muscle), heart, and aorta were removed from Dmp1 null mice and ex-vivo functional tests were simultaneously performed in collaboration by three different laboratories. Dmp1 null EDL and SOL muscles produced less force than wildtype muscles after normalization for physiological cross sectional area of the muscles. Both EDL and SOL muscles from Dmp1 null mice also produced less force after the addition of caffeine (which releases calcium from the sarcoplasmic reticulum) which may indicate problems in excitation contraction coupling in these mice. While the body weights of the Dmp1 null were smaller than wildtype, the heart weight to body weight ratio was higher. However, there were no differences in pathological hypertrophic gene expression compared to wildtype and maximal force of contraction was not different indicating that there may not be cardiac pathology under the tested conditions. We did observe a decrease in the rate of force development generated by cardiac muscle in the Dmp1 null which may be related to some of the deficits observed in skeletal muscle. There were no differences observed in aortic contractions induced by PGF2α or 5-HT or in endothelium-mediated acetylcholine-induced relaxations or endothelium-independent sodium nitroprusside-induced relaxations. In summary, these results indicate that there are deficiencies in both fast twitch and slow twitch muscle fiber type contractions in this model of ARHR, while there was less of a phenotype observed in cardiac muscle, and no differences observed in aortic function. These results may help explain skeletal muscle weakness reported by some patients with osteomalacia and need to be further investigated.

Cardiovascular Interactions between Fibroblast Growth Factor-23 and Angiotensin II

“…We also have found that β-Mhc expression was significantly increased in heart from Hyp mice (Fig. 4E ), which is similar to findings from Dmp1 knockout mice, another hereditary model of excess FGF-23 48 . Moreover, the observation that elevations of FGF-23 exacerbate the severity of Ang II-induced hypertension and LVH in the Hyp mouse model, indicates that FGF-23 and RAAS may work through complementary pathways to enhance cardiovascular responses.…”

FGF23 Actions on Target Tissues—With and Without Klotho

“…However, another clinical study challenges this view ( 195 ). Furthermore, it has been shown that genetic mouse models for XLH and autosomal recessive hypophosphatemic rickets (ARHR) show an increase in cardiac mass, while cardiac functions seems to be normal ( 172 , 173 , 196 ). Overall, primary forms of pathologic cardiac remodeling might not require FGF23, and not every scenario of FGF23 elevations might result in cardiac hypertrophy.…”

“…Since FGF23 can directly induce injury of the heart muscle, it is tempting to speculate that FGF23 might also contribute to skeletal muscle dysfunction and atrophy that is found in many patients with CKD ( 254 ). Interestingly, animal models for ARHR and XLH with primary FGF23 elevations show deficiencies in skeletal muscle fiber contraction and develop muscle weakness, which is ameliorated after injections of an FGF23-blocking antibody ( 196 , 255 ). FGF23 might also have beneficial effects on skeletal muscle, as elevations of circulating FGF23 by intraperitoneal injections of recombinant FGF23 in wild-type mice extends exercise performance ( 256 ).…”

Slc20a1/Pit1 and Slc20a2/Pit2 are essential for normal skeletal myofiber function and survival

“…Interestingly, GS is not affected in mice lacking two or three transporter alleles, which is different from observations in the Hyp mouse model for XLH that displays reduced GS along with reduced VWR activity, and which both are restored by treatment of Hyp mice with anti-FGF23 antibodies 36 . Likewise, ex-vivo tetanic strength was impaired in Dmp1 null mice 38 , which like Hyp have elevated FGF23 levels. It is thus conceivable that FGF23 impacts skeletal muscle function 33 similar to its effect on the cardiac muscle 32 .…”

“…Likewise, the Hyp mouse model for XLH has reduced running activity and grip strength, and anti-FGF23 antibodies restore normophosphatemia, endurance and grip strength 36 . Although no short-term effect of FGF23 on muscle function was reported in ex vivo settings 37 , chronic exposure to this hormone may be negative for muscle strength as shown in Dmp1 null mice 38 , which like Hyp mice have FGF23-dependent hypophosphatemia. In addition, in vitamin D-deficient individuals, cholecalciferol therapy was shown to improve mitochondrial activity and restore muscle function 39,40 .…”