Key points Dietary supplementation with inorganic nitrate has beneficial effects on skeletal muscle responses to exercise. Both mitochondrial and extra‐mitochondrial explanations have been proposed. Contractile force of fast‐twitch muscles was enhanced in mice supplemented with 1 mm NaNO3 in drinking water for 7 days. Myoplasmic free [Ca2+] during tetanic stimulation was increased in fast‐twitch muscles of nitrate‐supplemented mice and this was accompanied by increased expression of calsequestrin 1 and the dihydropyridine receptor. These results provide a new mechanism by which nitrate exerts beneficial effects on muscle function with applications to sports performance and a potential therapeutic role in conditions with muscle weakness. Abstract  Dietary inorganic nitrate has profound effects on health and physiological responses to exercise. Here, we examined if nitrate, in doses readily achievable via a normal diet, could improve Ca2+ handling and contractile function using fast‐ and slow‐twitch skeletal muscles from C57bl/6 male mice given 1 mm sodium nitrate in water for 7 days. Age matched controls were provided water without added nitrate. In fast‐twitch muscle fibres dissected from nitrate treated mice, myoplasmic free [Ca2+] was significantly greater than in Control fibres at stimulation frequencies from 20 to 150 Hz, which resulted in a major increase in contractile force at ≤50 Hz. At 100 Hz stimulation, the rate of force development was ∼35% faster in the nitrate group. These changes in nitrate treated mice were accompanied by increased expression of the Ca2+ handling proteins calsequestrin 1 and the dihydropyridine receptor. No changes in force or calsequestrin 1 and dihydropyridine receptor expression were measured in slow‐twitch muscles. In conclusion, these results show a striking effect of nitrate supplementation on intracellular Ca2+ handling in fast‐twitch muscle resulting in increased force production. A new mechanism is revealed by which nitrate can exert effects on muscle function with applications to performance and a potential therapeutic role in conditions with muscle weakness.

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BackgroundOnline haemodiafiltration (OL-HDF) has been shown to reduce all-cause mortality versus conventional haemodialysis (HD); however, it is not always available. In these situations, a novel class of membranes with a higher pore size, medium cut-off (MCO) dialysers, could be promising. The aim of this study is to evaluate the efficacy of an MCO dialyser in the removal of small and medium-size molecules and compare it with standard high-flux (HF) dialysers in HD and OL-HDF.MethodsIn this crossover study, 18 prevalent HD patients were studied in three single mid-week dialysis treatments during three consecutive weeks as follows: first week with OL-HDF with a standard HF dialyser, second week with conventional HD with a standard HF dialyser and third week with conventional HD with an MCO dialyser. Reduction ratios (RRs) of different-sized molecules and albumin losses were collected for the different dialysers.ResultsMCO HD provided a greater reduction of middle and larger middle molecules compared with standard HF HD [rate reduction (RR) β2-microglobulin 74.7% versus 69.7%, P=0.01; RR myoglobin 62.5% versus 34.3%, P=0.001; RR prolactin 60% versus 32.8%, P=0.001; RR α1-glycoprotein 2.8% versus −0.1%, P=0.01]. We found no difference in the clearance of small and larger middle molecules comparing MCO HD with OL-HDF. Albumin losses were 0.03  g/session with MCO HD and 3.1  g/session with OL-HDF (P=0.001).ConclusionMCO HD is superior to standard HF HD in the removal of middle and larger middle molecules and it is not inferior to OL-HDF in the clearance of small and larger middle molecules. Thus it could be an alternative in patients in which it is not possible to perform OL-HDF.

NP prevalence in cancer pain is 33%. DN4 reports only about half the cancer NP cases diagnosed by clinicians. Pharmaceutical treatment of cancer pain, including NP, has a greater effect in patients with metastases and seems to depend on the specific treatment used.

Muscle weakness and exercise intolerance are hallmark symptoms in mitochondrial disorders. Little is known about the mechanisms leading to impaired skeletal muscle function and ultimately muscle weakness in these patients. In a mouse model of lethal mitochondrial myopathy, the muscle-specific Tfam knock-out (KO) mouse, we previously demonstrated an excessive mitochondrial Ca(2+) uptake in isolated muscle fibers that could be inhibited by the cyclophilin D (CypD) inhibitor, cyclosporine A (CsA). Here we show that the Tfam KO mice have increased CypD levels, and we demonstrate that this increase is a common feature in patients with mitochondrial myopathy. We tested the effect of CsA treatment on Tfam KO mice during the transition from a mild to terminal myopathy. CsA treatment counteracted the development of muscle weakness and improved muscle fiber Ca(2+) handling. Importantly, CsA treatment prolonged the lifespan of these muscle-specific Tfam KO mice. These results demonstrate that CsA treatment is an efficient therapeutic strategy to slow the development of severe mitochondrial myopathy.