Altered skeletal muscle glucose-fatty acid flux in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is characterized by the degeneration of upper and lower motor neurons, yet an increasing number of studies in both mouse models and patients with amyotrophic lateral sclerosis suggest that altered metabolic homeostasis is also a feature of disease. Pre-clinical and clinical studies have shown that modulation of energy balance can be beneficial in amyotrophic lateral sclerosis. However, the capacity to target specific metabolic pathways or mechanisms requires detailed understanding of metabolic dysregulation in amyotrophic lateral sclerosis. Here, using the superoxide dismutase 1, glycine to alanine substitution at amino acid 93 (SOD1G93A) mouse model of amyotrophic lateral sclerosis, we demonstrate that an increase in whole-body metabolism occurs at a time when glycolytic muscle exhibits an increased dependence on fatty acid oxidation. Using myotubes derived from muscle of amyotrophic lateral sclerosis patients, we also show that increased dependence on fatty acid oxidation is associated with increased whole-body energy expenditure. In the present study, increased fatty acid oxidation was associated with slower disease progression. However, within the patient cohort, there was considerable heterogeneity in whole-body metabolism and fuel oxidation profiles. Thus, future studies that decipher specific metabolic changes at an individual patient level are essential for the development of treatments that aim to target metabolic pathways in amyotrophic lateral sclerosis.

The median eminence detects and responds to circulating prolactin in the male mouse.

In addition to its established lactational roles, prolactin acts on multiple target tissues and its circulating levels are responsive to a range of physiological stimuli. The present study used immunohistochemistry to demonstrate that systemic administration of prolactin activates target cells in the arcuate nucleus and median eminence of the male mouse. Prolactin receptor stimulation results in the phosphorylation and thus activation of the signal transducer and activator of transcription (STAT)5 pathway. Interestingly, although, in the arcuate nucleus, this response was localised to cell nuclei, the median eminence displayed both nuclear and diffuse, non-nuclear, phospho-STAT5 (pSTAT5) staining. Dual-label immunostaining demonstrated that, although the majority of nuclear pSTAT5 within the median eminence was located within vimentin-positive tanycytes, the non-nuclear staining occurred primarily in neuronal (ßIII tubulin immunoreactive) elements. This conclusion was supported by the marked reduction of this signal in prolactin-treated mice lacking neuronal prolactin receptors. A smaller reduction was also seen in animals lacking prolactin receptors on GABAergic but not glutamatergic neurones. These findings identify a new prolactin target tissue and, in doing so, support the proposal that the median eminence has a sensory role in addition to its established secretory function. The physiological significance of this prolactin response is unknown, although its rapidity (maximum within 2 minutes of i.p. injection) suggests that it may enable the early detection of an increase in circulating prolactin. It is also possibile that non-nuclear prolactin-generated pSTAT5 in the median eminence may have a local, non-transcriptional, action. To this end, we used Evans Blue dye to demonstrate that elevated prolactin appears to reduce median eminence permeability and also that this effect is lost in animals lacking neuronal prolactin receptors.

Biomarkers of Metabolism in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the deterioration of motor neurons. However, this complex disease extends beyond the boundaries of the central nervous system, with metabolic alterations being observed at the systemic and cellular level. While the number of studies that assess the role and impact of metabolic perturbations in ALS is rapidly increasing, the use of metabolism biomarkers in ALS remains largely underinvestigated. In this review, we discuss current and potential metabolism biomarkers in the context of ALS. Of those for which data does exist, there is limited insight provided by individual markers, with specificity for disease, and lack of reproducibility and efficacy in informing prognosis being the largest drawbacks. However, given the array of metabolic markers available, the potential exists for a panel of metabolism biomarkers, which may complement other current biomarkers (including neurophysiology, imaging, as well as CSF, blood and urine markers) to overturn these limitations and give rise to new diagnostic and prognostic indicators.