Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity.

Endurance exercise promotes skeletal muscle vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. Importantly, the metabolic and contractile properties of the muscle fiber must be coupled to the identity of the innervating motor neuron (MN). Here, we show that muscle-derived neurturin (NRTN) acts on muscle fibers and MNs to couple their characteristics. Using a muscle-specific NRTN transgenic mouse (HSA-NRTN) and RNA sequencing of MN somas, we observed that retrograde NRTN signaling promotes a shift toward a slow MN identity. In muscle, NRTN increased capillary density and oxidative capacity and induced a transcriptional reprograming favoring fatty acid metabolism over glycolysis. This combination of effects on muscle and MNs makes HSA-NRTN mice lean with remarkable exercise performance and motor coordination. Interestingly, HSA-NRTN mice largely recapitulate the phenotype of mice with muscle-specific expression of its upstream regulator PGC-1ɑ1. This work identifies NRTN as a myokine that couples muscle oxidative capacity to slow MN identity.

Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions.

Fibrotic scar tissue limits central nervous system regeneration in adult mammals. The extent of fibrotic tissue generation and distribution of stromal cells across different lesions in the brain and spinal cord has not been systematically investigated in mice and humans. Furthermore, it is unknown whether scar-forming stromal cells have the same origin throughout the central nervous system and in different types of lesions. In the current study, we compared fibrotic scarring in human pathological tissue and corresponding mouse models of penetrating and non-penetrating spinal cord injury, traumatic brain injury, ischemic stroke, multiple sclerosis and glioblastoma. We show that the extent and distribution of stromal cells are specific to the type of lesion and, in most cases, similar between mice and humans. Employing in vivo lineage tracing, we report that in all mouse models that develop fibrotic tissue, the primary source of scar-forming fibroblasts is a discrete subset of perivascular cells, termed type A pericytes. Perivascular cells with a type A pericyte marker profile also exist in the human brain and spinal cord. We uncover type A pericyte-derived fibrosis as a conserved mechanism that may be explored as a therapeutic target to improve recovery after central nervous system lesions.

Comparative Analysis of Skeletal Muscle Transcriptional Signatures Associated With Aerobic Exercise Capacity or Response to Training in Humans and Rats.

Increasing exercise capacity promotes healthy aging and is strongly associated with lower mortality rates. In this study, we analyzed skeletal muscle transcriptomics coupled to exercise performance in humans and rats to dissect the inherent and response components of aerobic exercise capacity. Using rat models selected for intrinsic and acquired aerobic capacity, we determined that the high aerobic capacity muscle transcriptome is associated with pathways for tissue oxygenation and vascularization. Conversely, the low capacity muscle transcriptome indicated immune response and metabolic dysfunction. Low response to training was associated with an inflammatory signature and revealed a potential link to circadian rhythm. Next, we applied bioinformatics tools to predict potential secreted factors (myokines). The predicted secretome profile for exercise capacity highlighted circulatory factors involved in lipid metabolism and the exercise response secretome was associated with extracellular matrix remodelling. Lastly, we utilized human muscle mitochondrial respiration and transcriptomics data to explore molecular mediators of exercise capacity and response across species. Human transcriptome comparison highlighted epigenetic mechanisms linked to exercise capacity and the damage repair for response. Overall, our findings from this cross-species transcriptome analysis of exercise capacity and response establish a foundation for future studies on the mechanisms that link exercise and health.

Bidirectional regulation of Aß levels by Presenilin 1.

Alzheimer's disease (AD) is characterized by accumulation of the ß-amyloid peptide (Aß), which is generated through sequential proteolysis of the amyloid precursor protein (APP), first by the action of ß-secretase, generating the ß-C-terminal fragment (ßCTF), and then by the Presenilin 1 (PS1) enzyme in the γ-secretase complex, generating Aß. γ-Secretase is an intramembranous protein complex composed of Aph1, Pen2, Nicastrin, and Presenilin 1. Although it has a central role in the pathogenesis of AD, knowledge of the mechanisms that regulate PS1 function is limited. Here, we show that phosphorylation of PS1 at Ser367 does not affect γ-secretase activity, but has a dramatic effect on Aß levels in vivo. We identified CK1γ2 as the endogenous kinase responsible for the phosphorylation of PS1 at Ser367. Inhibition of CK1γ leads to a decrease in PS1 Ser367 phosphorylation and an increase in Aß levels in cultured cells. Transgenic mice in which Ser367 of PS1 was mutated to Ala, show dramatic increases in Aß peptide and in ßCTF levels in vivo. Finally, we show that this mutation impairs the autophagic degradation of ßCTF, resulting in its accumulation and increased levels of Aß peptide and plaque load in the brain. Our results demonstrate that PS1 regulates Aß levels by a unique bifunctional mechanism. In addition to its known role as the catalytic subunit of the γ-secretase complex, selective phosphorylation of PS1 on Ser367 also decreases Aß levels by increasing ßCTF degradation through autophagy. Elucidation of the mechanism by which PS1 regulates ßCTF degradation may aid in the development of potential therapies for Alzheimer's disease.

Modulation of Autophagy as a Therapeutic Target for Alzheimer's Disease.

Macroautophagy (autophagy) is a conserved cellular pathway that regulates the degradation of long-lived proteins, protein aggregates, and cellular organelles. Autophagy is essential for maintaining neuronal homeostasis; however, neuronal autophagic efficiency decreases with age. Therefore, aging is one of the greatest risk factors for development of Alzheimer's disease (AD), a slowly progressing form of neurodegeneration that develops over the course of 10-20 years prior to the onset of overt clinical symptoms. AD is defined neuropathologically by the presence of extracellular aggregates of the amyloidogenic protein amyloid-ß (Aß) and intracellular accumulation of the microtubule-associated protein tau. At end-stage Alzheimer's disease, abnormal autophagic pathology has been reported in human brain and in multiple mouse models of AD, suggesting that an intimate association may exist between neuronal autophagy stasis and Alzheimer's-related pathology. Here, we highlight recent evidence that the autophagic pathway plays a role in both the generation and clearance of the pathogenic Aß protein and its precursors. The primary focus of this review is to examine the compelling research that highlights the autophagic pathway as a therapeutic target for AD and to discuss the therapeutic space around autophagy-regulating programs for AD. Finally, we propose that programs targeting autophagy regulation for AD ought to consider prophylactic or early stage intervention trials based on evidence against druggability of this pathway in late-stage disease.