The translationally controlled tumor protein (TCTP) is upregulated in a range of cancer cell types, in part, by the activation of the mechanistic target of rapamycin (mTOR). Recently, TCTP has also been proposed to act as an indirect activator of mTOR. While it is known that mTOR plays a major role in the regulation of skeletal muscle mass, very little is known about the role and regulation of TCTP in this post-mitotic tissue. This study shows that muscle TCTP and mTOR signaling are upregulated in a range of mouse models (mdx mouse, mechanical load-induced hypertrophy, and denervation- and immobilization-induced atrophy). Furthermore, the increase in TCTP observed in the hypertrophic and atrophic conditions occurred, in part, via a rapamycin-sensitive mTOR-dependent mechanism. However, the overexpression of TCTP was not sufficient to activate mTOR signaling (or increase protein synthesis) and is thus unlikely to take part in a recently proposed positive feedback loop with mTOR. Nonetheless, TCTP overexpression was sufficient to induce muscle fiber hypertrophy. Finally, TCTP overexpression inhibited the promoter activity of the muscle-specific ubiquitin proteasome E3-ligase, MuRF1, suggesting that TCTP may play a role in inhibiting protein degradation. These findings provide novel data on the role and regulation of TCTP in skeletal muscle in vivo.

Mitochondrial dysfunction is a pathological feature of Duchenne muscular dystrophy (DMD), a debilitating and fatal neuromuscular disorder characterized by progressive muscle wasting and weakness. Mitochondria are a source of cellular ATP involved in Ca regulation and apoptotic signaling. Ameliorating aberrant mitochondrial function has therapeutic potential for reducing DMD disease severity. The dystrophic mdx mouse exhibits peak muscle damage at 21-28 days, which stabilizes after 8 wk. The amino acid taurine is implicated in mitochondrial health and function, with endogenous concentrations low when measured during the cycle of peak muscle damage in mdx mice. Using whole soleus and extensor digitorum longus (EDL) muscle homogenates from 28- and 70-day mdx mice, we found that there was no change in native state mitochondrial complexes using blue native-PAGE. NADH:ubiquinone oxidotreductase subunit-A9 (NDUFA9) protein abundance was lower in soleus muscle of 28- and 70-day mdx mice and EDL muscle of 70-day mdx mice compared with same muscles in WT (C57/BL10ScSn) animals. There were age-dependent increases in both NDUFA9 protein abundance and citrate synthase activity in soleus muscles of mdx and wild-type mice. There was no change in abundances of mitochondrial dynamics proteins mitofusin 2 (Mfn2) and mitochondrial dynamics protein 49 (MiD49). Taurine administration essentially did not affect any measurements of mitochondria. Collectively, these findings suggest mitochondrial content and dynamics are not reduced in the mdx mouse regardless of disease severity. We also elucidate that taurine affords no significant benefit to mitochondrial content or dynamics in the mdx mouse at either 28 or 70 days.

Introduction:Duchenne Muscular Dystrophy (DMD) is a debilitating muscle wasting disorder with no cure. Safer supplements and therapies are needed to improve the severity of symptoms, as severe side effects are associated with the only effective treatment, corticosteroids. The amino acid taurine has shown promise in ameliorating dystrophic symptoms in mdx mice, an animal model of DMD, however little work is in 21-28 (d)ay animals, the period of natural peak damage.Methods:This study compares the effect of prenatal taurine supplementation on tibialis anterior (TA) in situ contractile function, histopathological characteristics and the abundance of Ca2+-handling as well as pathologically relevant proteins in non-exercised mdx mice at 28 and 70 d.Results:Supplementation elevated TA taurine content by 25% (p<0.05), ameliorated in situ specific force by 60% (p<0.05) and improved histological characteristics in 28 d mdx mice; however no benefit was seen in 70 d mice, where background pathology was initially stable. Age specific effects in SERCA1, calsequestrin 1 (CSQ1), CSQ2, utrophin and myogenin protein abundances were seen between both 28 and 70 d mdx and mdx taurine-supplemented mice.Discussion:Considering these findings and that taurine is a relatively cost effective, readily accessible and side effect free dietary supplement, we propose further investigation into taurine supplementation during pregnancy in a protective capacity, reminiscent of folate in the prevention of spinal bifida.

An increasing number of studies have shown supplementation with the amino acid taurine to have promise in ameliorating dystrophic symptoms in the mdx mouse model of Duchenne Muscular Dystrophy (DMD). Here we build on this limited body of work by investigating the efficacy of supplementing mdx mice with taurine postnatally at a time suggestive of when dystrophic symptoms would begin to manifest in humans, and when treatments would likely begin. Mdx mice were given either taurine (mdx tau), the steroid alpha methylprednisolone (PDN), or tau + PDN (mdx tau + PDN). Taurine (2.5% wt/vol) enriched drinking water was given from 14 days and PDN (1 mg/kg daily) from 18 days. Wild-type (WT, C57BL10/ScSn) mice were used as a control to mdx mice to represent healthy tissue. In the mdx mouse, peak damage occurs at 28 days, and in situ assessment of contractile characteristics showed that taurine, PDN, and the combined taurine + PDN treatment was ineffective at attenuating the force loss experienced by mdx mice. Given the benefits of taurine as well as methylprednisolone reported previously, when supplemented at close proximity to the onset of severity muscle degeneration these benefits are no longer apparent.

ABSTRACT