Models of Hypophosphatemia and Phosphate Depletion

Knöchel, James P.

doi:10.1007/978-1-4684-4259-5_25

Cited by 5 publications

(2 citation statements)

References 7 publications

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“…Three allele mutants display reduced VWR activity which further supports the hypothesis that Pit1 and Pit2 are important predominantly for slow twitch fibers [4][5][6]58 as already suggested by the possible shift from fast Myh4 positive fibers to slow Myh7 positive fibers in quadriceps muscle of smPit1 −/− ; smPit2 −/− mice. Furthermore, subtle deficiencies in running wheel endurance were also observed in the single conditional mutant smPit1 −/− and smPit2 −/− mice, which may have been previously missed during evaluation of the global knockouts for these genes [15][16][17][18][19] .…”

Section: Discussionsupporting

confidence: 85%

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

Chande

Caballero

et al. 2020

Sci Rep

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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 housekeeping 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. Inorganic phosphate (Pi) is involved in various cellular processes including DNA and cell membrane synthesis, signal transduction, ATP production, and bone mineralization. Serum Pi is regulated by a hormonal bone-parathyroid-kidney axis consisting of fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and 1,25(OH) 2-D (calcitriol) 1. Familial disorders of Pi homeostasis are caused by mutations in components of this axis that either directly or indirectly (via homeostatic mechanisms) lower serum Pi levels. Furthermore, chronic hypophosphatemia is observed in the often vitamin D-, and therefore Pi-, deficient elderly population 2. How muscle weakness develops in these hypophosphatemic conditions, which Pi transporters are involved and whether the homeostatic hormonal changes, which develop as a result of hypophosphatemia, contribute to reduced muscle function is poorly understood. Previous studies suggest that decreased ATP 3,4 and phosphodiesters 5 may in part explain the muscle weakness seen in hypophosphatemia. We recently reported that hypophosphatemic myopathy goes along with reduced ATP flux (V ATP) 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. Basal and insulin-stimulated muscle V ATP and Pi uptake have furthermore been shown to be decreased in the offspring of patients with type 2 diabetes 7 .

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Section: Discussionsupporting

confidence: 85%

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

Chande

Caballero

et al. 2020

Sci Rep

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“…In pigs, only a few experimental studies have used a phosphate deficient diet (Aubel et al 1936, Filer et al 1966, although dietary phosphorus recommendations for growing swine are based on studies of biological characteristics at different levels op phosphorus intake (Koch & Mahan 1985). By supplementing a nonpurified diet with aluminium hydroxide, phosphate is lost through the feces and therefore escapes absorption (Spencer et al 1982, Knochel 1982. The aim of the present investigation was to study the consequences of hypophosphatemia in growing pigs.…”

Section: Hiiglin Et Almentioning

confidence: 98%