Epidemiology of spinal muscular atrophy caused by SMN1 deletions in Maritime Canada.

Spinal muscular atrophy (SMA), caused primarily by deletions in SMN1, leads to progressive loss of lower motor neurons. Newborn screening for SMA is under consideration for the Maritime Newborn Screening Program. The incidence of this disease has not been explored in Maritime Canada which includes the provinces of Nova Scotia (NS), New Brunswick (NB), and Prince Edward Island (PEI). In this retrospective chart review, patients were identified from the IWK Clinical Genomics Lab and Maritime Medical Genetics Service databases for SMN1 genetic testing between 2000 and 2020. The incidence of SMA in Maritime Canada was 1:11,900. Among patients born between 2000 and 2020, NB and PEI had lower proportions of type 1 SMA (12% and 0%, respectively) when compared to NS (50%). The majority of type 1 patients had 2 copies of SMN2, the majority of type 2 patients had 3 copies, and the majority of type 3 patients had 4 copies. There was a delay to molecular diagnosis for all subtypes, longest in type 3. This study provides the best available SMA epidemiology in Maritime Canada and expands our understanding of the pattern of disease severity relative to SMN2 copy number in this region.

AMPK Promotes Xenophagy through Priming of Autophagic Kinases upon Detection of Bacterial Outer Membrane Vesicles.

The autophagy pathway is an essential facet of the innate immune response, capable of rapidly targeting intracellular bacteria. However, the initial signaling regulating autophagy induction in response to pathogens remains largely unclear. Here, we report that AMPK, an upstream activator of the autophagy pathway, is stimulated upon detection of pathogenic bacteria, before bacterial invasion. Bacterial recognition occurs through the detection of outer membrane vesicles. We found that AMPK signaling relieves mTORC1-mediated repression of the autophagy pathway in response to infection, positioning the cell for a rapid induction of autophagy. Moreover, activation of AMPK and inhibition of mTORC1 in response to bacteria is not accompanied by an induction of bulk autophagy. However, AMPK signaling is required for the selective targeting of bacteria-containing vesicles by the autophagy pathway through the activation of pro-autophagic kinase complexes. These results demonstrate a key role for AMPK signaling in coordinating the rapid autophagic response to bacteria.

Cellular Biomechanics in Skeletal Muscle Regeneration.

Satellite cells, adult stem cells in skeletal muscle tissue, reside within a mechanically dynamic three-dimensional microenvironment. With each contraction-relaxation cycle, a satellite cell is expected to experience tensile, shear, and compressive stresses, and through cell-extracellular matrix interactions, also gauge the stiffness of the niche. Via mechanoreceptors, cells can sense these biophysical parameters of the niche, which serve to physically induce conformational changes that impact biomolecule activity, and thereby alter downstream signal transduction pathways and ultimately cell fate. An emerging body of literature supports the notion that myogenic cells, too, integrate biochemical factors together with biomechanical stresses and that this may serve to provide spatio-temporal control of cell fate in the complicated three-dimensional niche. Further, skeletal muscle regenerative medicine therapies are being improved by applying this fresh insight. In this focused chapter, the progression of skeletal muscle regeneration is dissected into a dynamic conversation between muscle progenitor cells and the mechanical properties of the extracellular matrix. The significance of biophysical regulation to myogenic repair is reinforced by the exaggerative influences of extrinsic mechanical stresses and the pathological implications of ECM dysregulation. Additional fundamental studies that further define the satellite cell biophysical environment in health, regeneration, aging, and disease may serve to close knowledge gaps and bolster skeletal muscle regenerative medicine.