Characterization of clathrin heavy chain 22 in epithelial and skeletal muscle cells

[no abstract

The CHC22 Clathrin-GLUT4 Transport Pathway Contributes to Skeletal Muscle Regeneration

Mobilization of the GLUT4 glucose transporter from intracellular storage vesicles provides a mechanism for insulin-responsive glucose import into skeletal muscle. In humans, clathrin isoform CHC22 participates in formation of the GLUT4 storage compartment in skeletal muscle and fat. CHC22 function is limited to retrograde endosomal sorting and is restricted in its tissue expression and species distribution compared to the conserved CHC17 isoform that mediates endocytosis and several other membrane traffic pathways. Previously, we noted that CHC22 was expressed at elevated levels in regenerating rat muscle. Here we investigate whether the GLUT4 pathway in which CHC22 participates could play a role in muscle regeneration in humans and we test this possibility using CHC22-transgenic mice, which do not normally express CHC22. We observed that GLUT4 expression is elevated in parallel with that of CHC22 in regenerating skeletal muscle fibers from patients with inflammatory and other myopathies. Regenerating human myofibers displayed concurrent increases in expression of VAMP2, another regulator of GLUT4 transport. Regenerating fibers from wild-type mouse skeletal muscle injected with cardiotoxin also showed increased levels of GLUT4 and VAMP2. We previously demonstrated that transgenic mice expressing CHC22 in their muscle over-sequester GLUT4 and VAMP2 and have defective GLUT4 trafficking leading to diabetic symptoms. In this study, we find that muscle regeneration rates in CHC22 mice were delayed compared to wild-type mice, and myoblasts isolated from these mice did not proliferate in response to glucose. Additionally, CHC22-expressing mouse muscle displayed a fiber type switch from oxidative to glycolytic, similar to that observed in type 2 diabetic patients. These observations implicate the pathway for GLUT4 transport in regeneration of both human and mouse skeletal muscle, and demonstrate a role for this pathway in maintenance of muscle fiber type. Extrapolating these findings, CHC22 and GLUT4 can be considered markers of muscle regeneration in humans

CHC22 clathrin mediates traffic from early secretory compartments for human GLUT4 pathway biogenesis

Post-prandial blood glucose is cleared by Glucose Transporter 4 (GLUT4) released from an intracellular GLUT4 storage compartment (GSC) to the surface of muscle and adipose tissue in response to insulin. Here we map the biosynthetic pathway for human GSC formation, which involves the clathrin isoform CHC22. We observe that GLUT4 transits more slowly through the early secretory pathway than the constitutively-secreted GLUT1 transporter, and show CHC22 colocalizes with p115 in the endoplasmic-reticulum-to-Golgi-intermediate compartment (ERGIC). We find CHC22 functions in membrane traffic from the early secretory pathway during formation of the replication vacuole of Legionella pneumophila, which also acquires components of the GLUT4 pathway. We show that p115 but not GM130 is required for GSC formation, indicating GSC biogenesis from the ERGIC bypasses the Golgi. This GSC biogenesis pathway is attenuated in mice, which lack CHC22, and rely mainly on recapture of surface GLUT4 to populate their GSC. GLUT4 traffic to the GSC is enhanced by CHC22 function at the human ERGIC, which has implications for pathways to insulin resistance

The clathrin heavy chain isoform CHC22 functions in a novel endosomal sorting step

CHC22 is needed for retrograde trafficking from endosomes to the trans-Golgi, unlike its clathrin sibling CHC17, and in a manner distinct from retromer

Vitamin C in plasma is inversely related to blood pressure and change in blood pressure during the previous year in young Black and White women

BackgroundThe prevalence of hypertension and its contribution to cardiovascular disease risk makes it imperative to identify factors that may help prevent this disorder. Extensive biological and biochemical data suggest that plasma ascorbic acid may be such a factor. In this study we examined the association between plasma ascorbic acid concentration and blood pressure (BP) in young-adult women.MethodsParticipants were 242 Black and White women aged 18-21 yr from the Richmond, CA, cohort of the National Heart, Lung and Blood Institute Growth and Health Study. We examined the associations of plasma ascorbic acid with BP at follow-up year 10, and with change in BP during the previous year.ResultsIn cross-sectional analysis, plasma ascorbic acid at year 10 was inversely associated with systolic BP and diastolic BP after adjusting for race, body mass index, education, and dietary intake of fat and sodium. Persons in the highest one-fourth of the plasma ascorbic acid distribution had 4.66 mmHg lower systolic BP (95% CI 1.10 to 8.22 mmHg, p = 0.005) and 6.04 mmHg lower diastolic BP (95% CI 2.70 to 9.38 mmHg, p = 0.0002) than those in the lowest one-fourth of the distribution. In analysis of the change in BP, plasma ascorbic acid was also inversely associated with change in systolic BP and diastolic BP during the previous year. While diastolic blood pressure among persons in the lowest quartile of plasma ascorbic acid increased by 5.97 mmHg (95% CI 3.82 to 8.13 mmHg) from year 9 to year 10, those in the highest quartile of plasma vitamin C increased by only 0.23 mmHg (95% CI -1.90 to +2.36 mmHg) (test for linear trend: p < 0.0001). A similar effect was seen for change in systolic BP, p = 0.005.ConclusionPlasma ascorbic acid was found to be inversely associated with BP and change in BP during the prior year. The findings suggest the possibility that vitamin C may influence BP in healthy young adults. Since lower BP in young adulthood may lead to lower BP and decreased incidence of age-associated vascular events in older adults, further investigation of treatment effects of vitamin C on BP regulation in young adults is warranted

Perturbation Simulations.

Rate of asymmetric division after day 11 reduced to one-half (blue) and one-tenth (black) of its original value. (B). Rate of symmetric division after day 11 reduced to one-half (blue) and one-tenth (black) of its original value. Rate of S -> A differentiations reduced accordingly to keep the net S-cell growth rate unchanged (C). Immediate differentiation of S-cells on day 11, no symmetric divisions. (PDF)</p