Domenico Tricarico
Department of Pharmacobiology, Faculty of Pharmacy via Orabona No. 4, 70120 Bari, Italy

https://doi.org/10.36866/pn.81.44

In a recent study in The Journal of Physiology we demonstrated for the first time that the metabolically regulated ATP-sensitive K+ channel (KATP) can regulate the atrophic process in fast- and slow-twitch rat skeletal muscle. The KATP channels are normally expressed in the sarcolemma and in mitochondrial membrane, sensing and coupling intracellular nucleotide composition with K+ efflux and membrane potential. Channel opening occurs in response to a reduction in the ATP/ADP ratio during metabolic stress, which is often associated with abnormal Ca2+ movements across the cell membrane or inner mitochondrial membrane.

The KATP macromolecule was first discovered in 1983 in cardiomyocytes and later found in pancreatic beta cells, vascular myocytes and more recently in neurons (Flagg et al. 2010). The channel belongs to the ABC transporter superfamily: it is an octameric complex formed by the inwardly rectifying K+ channel subunits (Kir6.1 and Kir6.2) and the regulatory sulfonylurea receptor subunits (SUR1, SUR2A and SUR2B). The SUR subunits carry the binding site for drugs and nucleotides as well as phosphorylation sites. Our previous reports showed an intense KATP channel activity also in mouse, rat and human fast-twitch skeletal muscles in isolated membrane patches in the absence of intracellular ATP (Tricarico et al. 1999; Flagg et al. 2010). In resting un-stimulated fibres, KATP channel activity contributes a few millivolts (3–4 mV) to the resting potential; however, large repolarizing KATP channel currents are observed following insulin stimulation or high-frequency action potential firing, thereby reducing fibre excitability during muscle fatigue. KATP channels therefore save the energy pool during metabolic stress and regulate glucose uptake into the fibres. Secondary defects in channel subunits are responsible for insulin resistance and for a neuromuscular disorder known as hypokalaemic periodic paralysis.

We now provide evidence that the KATP channels play a role in skeletal muscle plasticity, which is the ability of the tissue to adapt to new conditions such as disuse through changes in muscle fibre phenotype composition, fibre diameter and cellular metabolism. We made several observations: first, the molecular composition and properties of the KATP channels are muscle phenotype dependent and muscle specific. This means that the channel properties are related to the speed of contraction and strength, which are muscle phenotype-dependent properties, but are also related to morphological characteristics of the muscles such as length and mass, and with their anatomical location. In this respect, we found higher expression/activity of the Kir6.2/SUR2A or Kir6.2/SUR1 subunits in fast-twitch muscle as compared with slow-twitch muscle phenotypes and differences in the expression/activity of the KATP channel subunits have also been observed within fast-twitch muscle types (Tricarico et al. 2006). High expression of the SUR1 subunit has been observed in the flexor digitorum brevis muscle of the rat, which is a fast-twitch muscle with elevated oxidative metabolism devoted to the rapid movements of the extremities, but also in a slow-twitch soleus muscle, which has postural function. Second, in an accepted animal model of muscle disuse, we demonstrated that the characteristic slow-to-fast fibre transition occurring in the slow-twitch muscle is associated with an up-regulation of KATP channel subunits, while down-regulation of the Kir6.2/SUR1 subunits correlate with a reduction of the fibre diameters leading to extensive atrophy. The atrophy of fast- and slow-twitch rat skeletal muscle was also pharmacologically induced in vitro by glibenclamide, a widely used anti-diabetic drug that blocks the Kir6.2/SUR1 channel subunits. The effects of this drug were prevented by diazoxide, a well-known Kir6.2/SUR1 channel opener, supporting the involvement of this channel in the observed phenomenon. All these findings corroborate the idea that KATP channels sense the changes in the muscle phenotype and in the fibre trophism (Tricarico et al. 2010). Similar effects of glibenclamide and diazoxide were observed in other cell lines expressing Kir6.2/SUR1 subunits (Maedler et al. 2004, 2005).

Atrophy is a condition affecting both fast- and slow-twitch muscles, often showing different degrees of damage depending on muscle type and function. It is normally slowly reversible; for example, several months are needed to recover muscle strength and morphology in healthy individuals following partial arm or leg immobilization. Such immobilization can, in severe cases, lead to an irreversible impairment of muscle function. Atrophy is also observed following exposure to toxins, overdose of certain chemo-therapeutic drugs or corticosteroids abuse. It is a common symptom of the cachexia associated with these and other pathophysiological conditions. This process is generally considered to be caused by an imbalance between protein synthesis and degradation, in favour of the latter. Knowledge of the pathways responsible for atrophy is essential for prevention and appropriate therapy. Several intracellular factors responsible for atrophy have been identified that lead to the activation of proteolytic mechanisms and inhibition of protein synthesis (Sandri, 2008).

Our emerging idea is that KATP channel activity also has a role in the regulation or induction of the atrophic process in skeletal muscle. Generally, KATP channel opening, if coupled to the energy demand of the cells, is considered protective for the cells and mitochondria, while irreversible channel closure is cytotoxic. Therefore, SUR1 inhibitors may induce atrophy or contribute to the atrophic process in skeletal muscle fibres expressing this subunit. This is of relevance considering the prescribed combined anti-diabetic and chemo-therapeutic drug therapy for the treatment of diabetic patients affected by cancer or bacterial/virus infections.

References

Maedler K, Størling J, Sturis J, Zuellig RA, Spinas GA, Arkhammar PO et al. (2004). Glucose- and interleukin-1β-induced β-cell apoptosis requires Ca2+ influx and extracellular signal-regulated kinase (ERK) 1/2 activation and is prevented by a sulfonylurea receptor 1/inwardly rectifying K+ channel 6.2 (SUR/Kir6.2) selective potassium channel opener in human islets. Diabetes 53, 1706–1713.

Maedler K, Carr RD, Bosco D, Zuellig RA, Berney T & Donath MY (2005). Sulfonylurea induced β-cell apoptosis in cultured human islets. J Clin Endocrinol Metab 90, 501–506.

Flagg TP, Enkvetchakul D, Koster JC & Nichols CG (2010). Muscle KATP channels: recent insights to energy sensing and myoprotection. Physiol Rev 90, 799–829.

Sandri M (2008). Signaling in muscle atrophy and hypertrophy. Physiology (Bethesda) 23, 160–170.

Tricarico D, Mele A, Camerino GM, Bottinelli R, Brocca L, Frigeri A, Svelto M, George AL Jr & Conte Camerino D (2010). The KATP channel is a molecular sensor of atrophy in skeletal muscle. J Physiol 588, 773–784. http://jp.physoc.org/content/588/5/773.long

Tricarico D, Mele A, Lundquist AL, Desai RR, George AL Jr & Conte Camerino D (2006). Hybrid assemblies of ATP-sensitive K+ channels determine their muscle-type dependent biophysical and pharmacological properties. Proc Natl Acad Sci U S A 103, 1118–1123.

Tricarico D, Servidei S, Tonali P, Jurkat-Rott K & Conte Camerino DC (1999). Impairment of skeletal muscle adenosine triphosphate-sensitive K+ channels in patients with hypokalemic periodic paralysis. J Clin Invest 103, 675–682.