Abstract
Muscle wasting or sarcopenia contributes to morbidity and mortality in patients with cancer, renal failure, or heart failure, and in elderly individuals. Na+-K+-2Cl− cotransporter 1 (NKCC1) is highly expressed in mammalian skeletal muscle, where it contributes to the generation of membrane ion currents and potential. However, the physiologic function of NKCC1 in myogenesis is unclear. We investigated this issue using the NKCC1 inhibitors bumetanide and furosemide, which are commonly used loop diuretics. NKCC1 protein levels increased during C2C12 murine skeletal myoblast differentiation, similarly to those of the myogenic markers myogenin and myosin heavy chain (MHC). NKCC1 inhibitors markedly suppressed myoblast fusion into myotubes and the expression of myogenin and MHC. Furthermore, phosphorylated and total NKCC1 levels were elevated in mouse skeletal muscles after 6 weeks’ voluntary wheel running. Immunofluorescence analyses of myofiber cross-sections revealed more large myofibers after exercise, but this was impaired by daily intraperitoneal bumetanide injections (0.2 or 10 mg/kg/day). NKCC1 plays an essential role in myogenesis and exercise-induced skeletal muscle hypertrophy, and sarcopenia in patients with renal or heart failure may be attributable to treatment with loop diuretics.
Highlights
Previous studies on the role of NKCC1 in skeletal muscle have mainly focused on cell volume homeostasis in response to extracellular osmolality[13], and the physiologic role of NKCC1 in skeletal myogenesis is poorly understood
We investigated whether the NKCC1 inhibitors bumetanide and furosemide modulate in-vitro differentiation of C2C12 murine skeletal myoblasts and in-vivo exercise-induced muscle hypertrophy to clarify the role of NKCC1 in skeletal myogenesis and muscle hypertrophy
To clarify whether NKCC1 expression changes during the differentiation of C2C12 murine skeletal muscle cells, we examined the expression of total (t) and phosphorylated (p) NKCC1 together with myogenic markers using western blotting
Summary
Previous studies on the role of NKCC1 in skeletal muscle have mainly focused on cell volume homeostasis in response to extracellular osmolality[13], and the physiologic role of NKCC1 in skeletal myogenesis is poorly understood. We investigated whether the NKCC1 inhibitors bumetanide and furosemide modulate in-vitro differentiation of C2C12 murine skeletal myoblasts and in-vivo exercise-induced muscle hypertrophy to clarify the role of NKCC1 in skeletal myogenesis and muscle hypertrophy. This issue has clinical significance because loop diuretics are commonly administered to patients with heart or renal failure and may be associated with sarcopenia in these populations
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