Abstract
Low blood phosphate (Pi) reduces muscle function in hypophosphatemic disorders. Which Pi transporters are required and whether hormonal changes due to hypophosphatemia contribute to muscle function is unknown. To address these questions we generated a series of conditional knockout mice lacking one or both house-keeping Pi transporters Pit1 and Pit2 in skeletal muscle (sm), using the postnatally expressed human skeletal actin-cre. Simultaneous conditional deletion of both transporters caused skeletal muscle atrophy, resulting in death by postnatal day P13. smPit1−/−, smPit2−/− and three allele mutants are fertile and have normal body weights, suggesting a high degree of redundance for the two transporters in skeletal muscle. However, these mice show a gene-dose dependent reduction in running activity also seen in another hypophosphatemic model (Hyp mice). In contrast to Hyp mice, grip strength is preserved. Further evaluation of the mechanism shows reduced ERK1/2 activation and stimulation of AMP kinase in skeletal muscle from smPit1−/−; smPit2−/− mice consistent with energy-stress. Similarly, C2C12 myoblasts show a reduced oxygen consumption rate mediated by Pi transport-dependent and ERK1/2-dependent metabolic Pi sensing pathways. In conclusion, we here show that Pit1 and Pit2 are essential for normal myofiber function and survival, insights which may improve management of hypophosphatemic myopathy.
Highlights
Low blood phosphate (Pi) reduces muscle function in hypophosphatemic disorders
We recently reported that hypophosphatemic myopathy goes along with reduced ATP flux (VATP) and intracellular Pi in an individual with hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and in the sodium-Pi co-transporter Npt2a null mouse model of this disorder[6]
Recombination resulting in excision of exons 3 and 4 of Pit[1] and of exon 4 of Pit[2] in quadriceps, but not in kidney, gut, brain, lung and liver was confirmed by genomic polymerase chain reaction (PCR) (Fig. 1C) and consistent with previously reported expression of human skeletal actin (HSA)-Cre using Rosa26tomato reporter mice[44]
Summary
Low blood phosphate (Pi) reduces muscle function in hypophosphatemic disorders. Which Pi transporters are required and whether hormonal changes due to hypophosphatemia contribute to muscle function is unknown. Basal and insulin-stimulated muscle VATP and Pi uptake have been shown to be decreased in the offspring of patients with type 2 diabetes[7] While these studies support a direct role for Pi as a substrate for mitochondrial ATP production, it is not clear whether extracellular Pi needs to enter skeletal muscle to improve VATP and muscle function, and which Pi transporters and intracellular signaling pathways are involved. Muscle ablation of ERK1/2 isoforms using HSA-Cre results in severe atrophy of the soleus muscles, revealing their important role for the maintenance of myofibers and neuromuscular synapses in adult mice, in type 1 slow twitch fibers[27,28] It is not clear whether FGF23, PTH, and 1,25(OH)2-D can contribute to hypophosphatemic myopathy by directly affecting muscle function in a Pi transport-independent fashion. High levels of PTH have been shown to cause myopathy in mice independent of blood Pi, but the mechanism is not known[41,42]
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