Taurine is a natural amino acid present as free form in many mammalian tissues and in particular in skeletal muscle. Taurine exerts many physiological functions, including membrane stabilization, osmoregulation and cytoprotective effects, antioxidant and anti-inflammatory actions as well as modulation of intracellular calcium concentration and ion channel function. In addition taurine may control muscle metabolism and gene expression, through yet unclear mechanisms. This review summarizes the effects of taurine on specific muscle targets and pathways as well as its therapeutic potential to restore skeletal muscle function and performance in various pathological conditions. Evidences support the link between alteration of intracellular taurine level in skeletal muscle and different pathophysiological conditions, such as disuse-induced muscle atrophy, muscular dystrophy and/or senescence, reinforcing the interest towards its exogenous supplementation. In addition, taurine treatment can be beneficial to reduce sarcolemmal hyper-excitability in myotonia-related syndromes. Although further studies are necessary to fill the gaps between animals and humans, the benefit of the amino acid appears to be due to its multiple actions on cellular functions while toxicity seems relatively low. Human clinical trials using taurine in various pathologies such as diabetes, cardiovascular and neurological disorders have been performed and may represent a guide-line for designing specific studies in patients of neuromuscular diseases.

Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting disease caused by a loss of sarcolemmal bound dystrophin, which results in the death of the muscle fibers leading to the gradual depletion of skeletal muscle. There is significant evidence demonstrating that increasing levels of the dystrophin-related protein, utrophin, in mouse models results in sarcolemmal bound utrophin and prevents the muscular dystrophy pathology. The aim of this work was to develop a small molecule which increases the levels of utrophin in muscle and thus has therapeutic potential. We describe the in vivo activity of SMT C1100; the first orally bioavailable small molecule utrophin upregulator. Once-a-day daily-dosing with SMT C1100 reduces a number of the pathological effects of dystrophin deficiency. Treatment results in reduced pathology, better muscle physiology leading to an increase in overall strength, and an ability to resist fatigue after forced exercise; a surrogate for the six minute walk test currently recommended as the pivotal outcome measure in human trials for DMD. This study demonstrates proof-of-principle for the use of in vitro screening methods in allowing identification of pharmacological agents for utrophin transcriptional upregulation. The best compound identified, SMT C1100, demonstrated significant disease modifying effects in DMD models. Our data warrant the full evaluation of this compound in clinical trials in DMD patients.

A preclinical screening for prompt-to-use drugs that are safer than steroids and beneficial in Duchenne muscular dystrophy was performed. Compounds able to reduce calcium-induced degeneration (taurine or creatine 10% in chow) or to stimulate regeneration [insulin-like growth factor-1 (IGF-1); 50 or 500 μg/kg s.c.] were administered for 4 to 8 weeks to mdx mice undergoing chronic exercise on a treadmill, a protocol to worsen dystrophy progression. α-Methyl-prednisolone (PDN; 1 mg/kg) was used as positive control. The effects were evaluated in vivo on forelimb strength and in vitro electrophysiologically on the macroscopic chloride conductance (gCl), an index of degeneration-regeneration events in mdx muscles, and on the mechanical threshold, a calcium-sensitive index of excitation-contraction coupling. The exercise produced a significant weakness and an impairment of gCl, by further decreasing the already low value of degenerating diaphragm (DIA) and fully hampering the increase of gCl typical of regenerating extensor digitorum longus (EDL) mdx muscle. The already negative voltage threshold for contraction of mdx EDL was also slightly worsened. Taurine > creatine > IGF-1 counteracted the exercise-induced weakness. The amelioration of gCl was drug- and muscle-specific: taurine was effective in EDL, but not in DIA muscle; IGF-1 and PDN were fully restorative in both muscles, whereas creatine was ineffective. An acute effect of IGF-1 on gCl was observed in vitro in untreated, but not in IGF-1-treated exercised mdx muscles. Taurine > PDN > IGF-1, but not creatine, significantly ameliorated the negative threshold voltage values of the EDL fibers. The results predict a potential benefit of taurine and IGF-1 for treating human dystrophy.

In the human genome more than 400 genes encode ion channels, which are transmembrane proteins mediating ion fluxes across membranes. Being expressed in all cell types, they are involved in almost all physiological processes, including sense perception, neurotransmission, muscle contraction, secretion, immune response, cell proliferation and differentiation. Due to the widespread tissue distribution of ion channels and their physiological functions, mutations in genes encoding ion channel subunits, or their interacting proteins, are responsible for inherited ion channelopathies. These diseases can range from common to very rare disorders and their severity can be mild, disabling, or life-threatening. In spite of this, ion channels are the primary target of only about 5% of the marketed drugs suggesting their potential in drug discovery. The current review summarizes the therapeutic management of the principal ion channelopathies of central and peripheral nervous system, heart, kidney, bone, skeletal muscle and pancreas, resulting from mutations in calcium, sodium, potassium and chloride ion channels. For most channelopathies the therapy is mainly empirical and symptomatic, often limited by lack of efficacy and tolerability for a significant number of patients. Other channelopathies can exploit ion channel targeted drugs, such as marketed sodium channel blockers. Developing new and more specific therapeutic approaches is therefore required. To this aim, a major advancement in the pharmacotherapy of channelopathies has been the discovery that ion channel mutations lead to change in biophysics that can in turn specifically modify the sensitivity to drugs: this opens the way to a pharmacogenetics strategy, allowing the development of a personalized therapy with increased efficacy and reduced side effects. In addition, the identification of disease modifiers in ion channelopathies appears an alternative strategy to discover novel druggable targets.

Among the severe side effects induced by cisplatin chemotherapy, muscle wasting is the most relevant one. This effect is a major cause for a clinical decline of cancer patients, since it is a negative predictor of treatment outcome and associated to increased mortality. However, despite its toxicity even at low doses, cisplatin remains the first-line therapy for several types of solid tumors. Thus, effective pharmacological treatments counteracting or minimizing cisplatin-induced muscle wasting are urgently needed. The dissection of the molecular pathways responsible for cisplatin-induced muscle dysfunction gives the possibility to identify novel promising therapeutic targets. In this context, the use of animal model of cisplatin-induced cachexia is very useful. Here, we report an update of the most relevant researches on the mechanisms underlying cisplatin-induced muscle wasting and on the most promising potential therapeutic options to preserve muscle mass and function.