Insulin-like growth factor-1-dependent maintenance of neuronal metabolism through the phosphatidylinositol 3-kinase-Akt pathway is inhibited by C2-ceramide in CAD cells

Ceramide is a lipid second-messenger generated in response to stimuli associated with neurodegeneration that induces apoptosis, a mechanism underlying neuronal death in Parkinson's disease. We tested the hypothesis that insulin-like growth factor-1 (IGF-1) could mediate a metabolic response in CAD cells, a dopaminergic cell line of mesencephalic origin that differentiate into a neuronal-like phenotype upon serum removal, extend processes resembling neurites, synthesize abundant dopamine and noradrenaline and express the catecholaminergic biosynthetic enzymes tyrosine hydroxylase and dopamine beta-hydroxylase, and that this process was phosphatidylinositol 3-kinase (PI 3-K)-Akt-dependent and could be inhibited by C(2)-ceramide. The metabolic response was evaluated as real-time changes in extracellular acidification rate (ECAR) using microphysiometry. The IGF-1-induced ECAR response was associated with increased glycolysis, determined by increased NAD(P)H reduction, elevated hexokinase activity and Akt phosphorylation. C(2)-ceramide inhibited all these changes in a dose-dependent manner, and was specific, as it was not induced by the inactive C(2)-ceramide analogue C(2)-dihydroceramide. Inhibition of the upstream kinase, PI 3-K, also inhibited Akt phosphorylation and the metabolic response to IGF-1, similar to C(2)-ceramide. Decreased mitochondrial membrane potential occurred after loss of Akt phosphorylation. These results show that IGF-1 can rapidly modulate neuronal metabolism through PI 3-K-Akt and that early metabolic inhibition induced by C(2)-ceramide involves blockade of the PI 3-K-Akt pathway, and may compromise the first step of glycolysis. This may represent a new early event in the C(2)-ceramide-induced cell death pathway that could coordinate subsequent changes in mitochondria and commitment of neurons to apoptosis.     

Identification of prostate cancer modifier pathways using parental strain expression mapping

Inherited genetic risk factors play an important role in cancer. However, other than the Mendelian fashion cancer susceptibility genes found in familial cancer syndromes, little is known about risk modifiers that control individual susceptibility. Here we developed a strategy, parental strain expression mapping, that utilizes the homogeneity of inbred mice and genome-wide mRNA expression analyses to directly identify candidate germ-line modifier genes and pathways underlying phenotypic differences among murine strains exposed to transgenic activation of AKT1. We identified multiple candidate modifier pathways and, specifically, the glycolysis pathway as a candidate negative modulator of AKT1-induced proliferation. In keeping with the findings in the murine models, in multiple human prostate expression data set, we found that enrichment of glycolysis pathways in normal tissues was associated with decreased rates of cancer recurrence after prostatectomy. Together, these data suggest that parental strain expression mapping can directly identify germ-line modifier pathways of relevance to human disease.     

Truncus endurance, hip and ankle mobility and aerobic fitness in 15-year-old Norwegian adolescents in 1968 and 1997

This study compared the physical performance of adolescents in 1997 and 1968. The material included 1329 15-year-old Norwegian adolescents in Akershus county in Norway in 1968, and 1105 15-year-old adolescents in the same region in 1997. The investigations were supervised by the same conductor on both occasions, and used identical physical tests. The test battery included dynamic endurance of abdominal and low back muscles, hip flexion, ankle dorsiflexion and aerobic fitness. Compared with 1968, low back extension endurance in 1997 was almost 10% lower in both genders, the endurance of the abdominal muscles was 4.8% poorer among boys and 8.1% higher among girls and the ratio between abdominal and low back extension endurance was 11.8% higher among boys and 26.4% higher in girls. Compared with 1968, hip flexion in 1997 was 8.3% higher in girls, while ankle dorsiflexion and aerobic fitness in boys were 15% and 13.4% poorer, and 4.8% poorer and 2.5% higher in girls, respectively. The data indicate a general decline during one generation in physical performance among boys, a decline in low back endurance, truncus balance and ankle mobility among girls and in a higher abdominal endurance among girls.     

Different adaptations of alpha‐actinin isoforms to exercise training in rat skeletal muscles

Aim: Alpha (α)‐actinins are located in the skeletal muscle Z‐line and form actin–actin cross‐links. Mammalian skeletal muscle has two isoforms: α‐actinin‐2 and α‐actinin‐3. However, the response of α‐actinin to exercise training is little understood. Therefore, the current study examined the effects of exercise training on the expression level of two α‐actinin isoforms in skeletal muscles. Methods: Twelve male Wistar rats were assigned randomly to a control (C; n = 6) or exercise training (T; n = 6) group. After T animals were trained on an animal treadmill for 9 weeks, α‐actinin‐2 and α‐actinin‐3 levels in the plantaris, white and red gastrocnemius muscles were analysed. In addition, changes in the myosin heavy chain (MyHC) composition were assessed, and muscle bioenergetic enzyme activities were measured. Results: Results show that exercise training increased α‐actinin‐2 expression levels in all muscles (P < 0.05). However, no significant difference was found in α‐actinin‐3 expression levels between C and T animals. Subsequent MyHC analyses of all muscle showed an MyHC shift with direction from IIb to IIa. Furthermore, enzymatic analysis revealed that exercise training improved enzyme activities related to aerobic metabolism. Conclusion: The results of this study demonstrate that exercise training alters the expression level of α‐actinin at the isoform level. Moreover, the increase in expression levels of α‐actinin‐2 is apparently related to alteration of skeletal muscle: its aerobic capacity is improved.     

Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression

As the result of genetic alterations and tumor hypoxia, many cancer cells avidly take up glucose and generate lactate through lactate dehydrogenase A (LDHA), which is encoded by a target gene of c-Myc and hypoxia-inducible factor (HIF-1). Previous studies with reduction of LDHA expression indicate that LDHA is involved in tumor initiation, but its role in tumor maintenance and progression has not been established. Furthermore, how reduction of LDHA expression by interference or antisense RNA inhibits tumorigenesis is not well understood. Here, we report that reduction of LDHA by siRNA or its inhibition by a small-molecule inhibitor (FX11 [3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid]) reduced ATP levels and induced significant oxidative stress and cell death that could be partially reversed by the antioxidant N-acetylcysteine. Furthermore, we document that FX11 inhibited the progression of sizable human lymphoma and pancreatic cancer xenografts. When used in combination with the NAD⁺ synthesis inhibitor FK866, FX11 induced lymphoma regression. Hence, inhibition of LDHA with FX11 is an achievable and tolerable treatment for LDHA-dependent tumors. Our studies document a therapeutical approach to the Warburg effect and demonstrate that oxidative stress and metabolic phenotyping of cancers are critical aspects of cancer biology to consider for the therapeutical targeting of cancer energy metabolism.     

Glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme, is required for sperm motility and male fertility

Although glycolysis is highly conserved, it is remarkable that several unique isozymes in this central metabolic pathway are found in mammalian sperm. Glyceraldehyde 3-phosphate dehydrogenase-S (GAPDS) is the product of a mouse gene expressed only during spermatogenesis and, like its human ortholog (GAPD2), is the sole GAPDH isozyme in sperm. It is tightly bound to the fibrous sheath, a cytoskeletal structure that extends most of the length of the sperm flagellum. We disrupted Gapds expression by gene targeting to selectively block sperm glycolysis and assess its relative importance for in vivo sperm function. Gapds(-/-) males were infertile and had profound defects in sperm motility, exhibiting sluggish movement without forward progression. Although mitochondrial oxygen consumption was unchanged, sperm from Gapds(-/-) mice had ATP levels that were only 10.4% of those in sperm from WT mice. These results imply that most of the energy required for sperm motility is generated by glycolysis rather than oxidative phosphorylation. Furthermore, the critical role of glycolysis in sperm and its dependence on this sperm-specific enzyme suggest that GAPDS is a potential contraceptive target, and that mutations or environmental agents that disrupt its activity could lead to male infertility.     

Cancer metabolism: The Warburg effect today

One of the first studies on the energy metabolism of a tumour was carried out, in 1922, in the laboratory of Otto Warburg. He established that cancer cells exhibited a specific metabolic pattern, characterized by a shift from respiration to fermentation, which has been later named the Warburg effect. Considerable work has been done since then, deepening our understanding of the process, with consequences for diagnosis and therapy. This review presents facts and perspectives on the Warburg effect for the 21st century.     

Over 55 years of critical power: Fact or artifact?

This report aims to generate an evidence-based debate of the Critical Power (CP), or its analogous Critical Speed (CS), concept. Race times of top Spanish runners were utilized to calculate CS based on three (1500-m to 5000-m; CS_1.5-5km) and four (1500-m to 10000-m; CS_1.5-10km) distance performances. Male running world records from 1000 to 5000-m (CS_1-5km), 1000 to 10,000-m (CS_1-10km), 1000-m to half marathon (CS_{1km-half marathon}), and 1000-m to marathon (CS_1km-marathon) distance races were also utilized for CS calculations. CS_1.5-5km (19.62 km h^?1) and CS_1.5-10km (18.68 km h^?1) were different (p < 0.01), but both approached the average race speed of the longest distance chosen in the model, and were remarkably homogeneous among subjects (97% ±1% and 98% ±1%, respectively). Similar results were obtained using the world records. CS values progressively declined, until reaching a CS_1km-marathon value of 20.77 km h^?1 (10% lower than CS_1-5km). Each CS value approached the average speed of the longest distance chosen in the model (96.4%–99.8%). A power function better fitted the speed-time relationship compared with the standardized hyperbolic function. However, the horizontal asymptote of a power function is zero. This better approaches the classical definition of CP: the power output that can be maintained almost indefinitely without exhaustion. Beyond any sophisticated mathematical calculation, CS corresponds to 95%–99% of the average speed of the longest distance chosen as an exercise trial. CP could be considered a mathematical artifact rather than an important endurance performance marker. In such a case, the consideration of CP as a physiological “gold-standard” should be reevaluated.