{'fraction_non_alphanumeric': 0.04830091899978628, 'fraction_numerical': 0.032485573840564226, 'mean_word_length': 5.062176165803109, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
NO turns on Na,K‐ATPase in skeletal muscle

Tight regulation of Na,K-ATPase activity in skeletal muscle is essential for muscle function and wholebody homeostasis. Activity of Na,K-ATPase adapts dynamically to acute alterations in demands for Na and K transport in skeletal muscle. This is particularly important during muscle contractions, when increased activity of Na,K-ATPase opposes contraction-induced displacement of Na and K across sarcolemma and thereby maintains muscle excitability and contractility (Clausen 2003). To meet the challenge of setting activity of Na,K-ATPase appropriately to fluctuating functional demands, skeletal muscle possesses sophisticated regulatory machinery, which controls Na,K-ATPase in a timely and coordinated manner. The finding by Juel (2015) in this issue of Acta Physiologica that nitric oxide (NO) stimulates Na,K-ATPase in skeletal muscle provides an important novel insight into how skeletal muscle fine-tunes its Na,K-ATPase. NO, a free radical gas, is an endogenous mediator (Furchgott & Zawadzki 1980, Ignarro et al. 1987, Palmer et al. 1987) that plays major physiological roles in cardiovascular, nervous and immune systems (Pacher et al. 2007). Endogenous NO is synthesized from arginine by nitric oxide synthase (NOS), which exists in three types: type I or neuronal NOS (type I or nNOS), inducible NOS (type II or iNOS) and endothelial NOS (type III or eNOS). First evidence that skeletal muscle might be a site of NO synthesis came from experiments demonstrating expression and activity of NOS in rat and human skeletal muscle (Nakane et al. 1993, Kobzik et al. 1994). Skeletal muscle fibres express primarily nNOSl, a muscle-specific isoform of nNOS (Silvagno et al. 1996), but other types of NOS have also been detected (Stamler & Meissner 2001). Synthesis of NO from arginine was soon directly determined in isolated extensor digitorum longus (EDL) muscle (Balon & Nadler 1994). Importantly, NO synthesis in EDL muscle was markedly increased by electrical stimulation (Balon & Nadler 1994), which suggested a role for NO during muscle contractions. NO exerts its effects by activating soluble guanylate (guanylyl) cyclase (Arnold et al. 1977) (Fig. 1). Once activated by NO, guanylate cyclase produces cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (Arnold et al. 1977). In turn, cGMP activates protein kinase G (PKG), which triggers a cascade of signalling events (Francis et al. 2010). Besides activating the cGMP-PKG pathway, NO can also modulate protein function directly by covalent modifications, such as S-nitrosylation of cysteine residues and nitration of tyrosine residues (Fig. 1) (Stamler & Meissner 2001, Pacher et al. 2007, Hess & Stamler 2012). Juel examined these possibilities in detail and found that NO donor spermine NONOate activates Na,K-ATPase in isolated EDL muscle as well as in homogenates of white vastus lateralis (VL) muscle (Juel 2015). Na,K-ATPase is also activated by treating VL homogenates with cGMP. Conversely, spermine NONOate and cGMP do not alter the activity of Na,K-ATPase in purified membranes from VL muscle, thus indicating that these substances do not activate Na,K-ATPase directly (Juel 2015). Taken together, Juel’s results strongly suggest that NO activates Na,K-ATPase by stimulating cGMP-dependent signalling pathways. Interestingly, sodium nitroprusside, an NO donor, was previously shown to suppress depolarization of denervated diaphragm ex vivo (Urazaev et al. 1996). This effect was blocked by guanylate cyclase inhibitor DNQ as well as by NO scavengers. Although Na,K-ATPase activity was not measured, these results are consistent with NO-stimulated activation of Na,K-ATPase as reported by Juel (2015). Na,K-ATPase comprises the catalytic a subunit (a1–4), which hydrolyses ATP and binds Na and K ions, and b subunit (b1–3), which is essential for assembly, maturation and function of the a/b heterodimers (McDonough et al. 1990, Geering 2008). Unlike in most tissues, where the a1 isoenzymes predominate, the a2 isoenzymes are predominant in skeletal muscle (Lytton et al. 1985, Orlowski & Lingrel 1988, Shyjan & Levenson 1989). Activity of Na,K-ATPase in skeletal muscle is regulated by Na and K ions (Clausen et al. 1987, DiFranco et al. 2015), protein–protein interactions (Geering 2008, Heiny et al. 2010, Chibalin et al. 2012) and by covalent modifications of its a and/or b subunits (Benziane & Chibalin 2008, Benziane et al. 2012, Juel 2014, Juel et al. 2015). The most fundamental way to activate Na,K-ATPase is by elevating intracellular Na and/or extracellular K concentrations, which happens, for instance, because of the generation