Merg1a K+ channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway.

Skeletal muscle atrophy results from an imbalance in protein degradation and protein synthesis and occurs in response to injury, various disease states, disuse, and normal aging. Current treatments for this debilitating condition are inadequate. More information about mechanisms involved in the onset and progression of muscle atrophy is necessary for development of more effective therapies. Here we show that expression of the mouse ether-a-go-go related gene (Merg1a) K+ channel is up-regulated in skeletal muscle of mice experiencing atrophy as a result of both malignant tumor expression and disuse. Further, ectopic expression of Merg1a in vivo induces atrophy in healthy wt-bearing mice, while expression of a dysfunctional Merg1a mutant suppresses atrophy in hindlimb-suspended mice. Treatment of hindlimb-suspended mice with astemizole, a known Merg1a channel blocker, inhibits atrophy in these animals. Importantly, in vivo expression of Merg1a in mouse skeletal muscle activates the ubiquitin proteasome pathway that is responsible for the majority of protein degradation that causes muscle atrophy, yet expression of a dysfunctional Merg1a mutant decreases levels of ubiquitin-proteasome proteolysis. Thus, expression of Merg1a likely initiates atrophy by activating ubiquitin-proteasome proteolysis. This gene and its product are potential targets for prevention and treatment of muscle atrophy.

Effect of hypothyroidism on kinetics of metabolism of very-low-density lipoprotein in mares.

OBJECTIVE: To compare kinetics of the metabolism of very-low-density lipoprotein (VLDL) apolipoprotein B (apoB) before and after thyroidectomy in mares. ANIMALS: 5 healthy adult mares. PROCEDURE: Thyroidectomy was performed in euthyroid mares. Kinetics of VLDL apoB metabolism were measured before and after thyroidectomy by use of a bolus IV injection of 5,5,5-2H3 (98%) leucine (5 mg/kg) and subsequent isolation of labeled amino acid from plasma and VLDL. Labeled leucine was quantified by use of gas chromatography-mass spectrometry. Production rate (PR), delay time, and fractional catabolic rate (FCR) were calculated for the 2 forms of equine VLDL, apoB-48 VLDL, and apoB-100 VLDL. Plasma lipid concentrations were measured, and VLDL composition was determined. RESULTS: Physical appearance of horses was not altered by thyroidectomy. Significantly lower mean blood concentrations of thyroid hormones and non-esterified fatty acids were detected following thyroidectomy. Mean percentage of free cholesterol in VLDL was significantly higher after thyroidectomy. Mean plasma VLDL concentration or kinetics of apoB-48 or apoB-100 were not significantly altered by thyroidectomy. Mean +/- SEM PR was significantly lower (8.70 +/- 1.61 mg/kg/d) and mean delay time significantly longer (1.58 +/- 0.12 hours) for apoB-48 VLDL in euthyroid mares, compared with values for thyroidectomized mares (16.15 +/- 2.24 mg/kg/d and 0.93 +/- 0.10 hours, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Hypothyroidism did not significantly alter plasma VLDL concentrations or kinetics of VLDL apoB metabolism. Metabolism of apoB-48 VLDL differed significantly from that of apoB-100 VLDL in euthyroid mares.

Effects of hypothyroidism and withholding of feed on plasma lipid concentrations, concentration and composition of very-low-density lipoprotein, and plasma lipase activity in horses.

OBJECTIVE: To evaluate selected concentrations of blood lipids and lipase activities in euthyroid and hypothyroid horses deprived of feed for 96 hours. ANIMALS: 4 healthy adult mares and 4 thyroidectomized adult mares. PROCEDURE: Horses were deprived of feed for 96 hours. Blood samples were collected at 24-hour intervals and analyzed to determine concentrations of non-esterified fatty acid (NEFA), triglyceride (TG), total cholesterol (TC), and very-low-density lipoprotein (VLDL) as well as composition of VLDL. Plasma lipase activities were measured after feed was withheld for 96 hours and 12 days after resumption of feeding. RESULTS: Time significantly affected plasma NEFA, VLDL, TG, and TC concentrations in both groups of horses. During the 96-hour period, mean plasma concentrations of NEFA and VLDL increased 10-fold in euthyroid horses and increased 5-fold and 9-fold, respectively, in hypothyroid horses. Mean plasma TG concentrations increased 8-fold in both groups, and plasma TC concentrations significantly increased by 33 and 30%, respectively. Composition of VLDL was significantly affected by feed deprivation in euthyroid horses. Activities of lipoprotein lipase and hepatic lipase were significantly higher in feed-deprived horses. Activity of hepatic lipase was significantly lower in hypothyroid horses than in euthyroid horses. CONCLUSIONS AND CLINICAL RELEVANCE: Hypothyroidism did not significantly alter the magnitude of the response of blood lipids to feed deprivation. Thyroid hormones may reduce variability in blood lipid concentrations but do not determine susceptibility to hyperlipemia. Hypothyroidism does not appear to be a factor in the pathogenesis of hyperlipemia in horses.

The circulating levels of lipoproteins in embryos and newly hatched ducklings change with parental age.

The purpose of this study was to investigate the effects of duck breeder age on circulating very low density lipoprotein (VLDL) and low-density lipoprotein (LDL) levels in embryonic (day 25 of incubation) and newly hatched ducklings (hatch and 1, 2, 3, and 5 days after hatch). In this study, embryos and ducklings from one breeder flock were monitored at breeder ages 24 weeks (young breeders), 31 weeks (mature breeders and near peak egg production), and 47 weeks (after peak egg production). Embryos and newly hatched ducklings from young breeders (24 weeks of age) displayed lower levels of VLDL and LDL. The composition of VLDL was affected by breeder age such that embryos and ducklings from young breeders had less cholesterol ester/protein and triglyceride/protein ratios. Even though the overall levels were suppressed in embryos and newly hatched ducklings from 24-week-old breeders, the overall percentage of triglyceride within VLDL and LDL particles was higher. These data would suggest that breeder age affects concentration and composition of both VLDL and LDL in embryos and newly hatched ducklings.

Effect of withholding feed on concentration and composition of plasma very low density lipoprotein and serum nonesterified fatty acids in horses.

OBJECTIVE: To measure and compare the concentration and composition of very low-density lipoprotein (VLDL) in plasma and selected lipids in serum of horses fed mixed grass hay ad libitum or denied feed for 36 hours. ANIMALS: 4 healthy adult mares. PROCEDURE: Mares were either fed mixed grass hay ad libitum or denied feed for 36 hours beginning at 8:00 AM. Blood samples were collected every 2 hours during the study period and analyzed for nonesterified fatty acid (NEFA), triglyceride (TG), VLDL, and glucose concentrations and composition of VLDL. RESULTS: Withholding feed significantly increased mean serum concentrations of NEFA. By 36 hours, a 16-fold increase in mean serum NEFA concentration and 2-fold increase in mean plasma VLDL concentration, compared with baseline values, were detected. Mean plasma TG concentrations significantly increased with time in feed-deprived horses. Significantly lower overall mean plasma glucose concentrations were detected in feed-deprived horses. Mean percentage of protein in VLDL was significantly lower in feed-deprived horses. Plasma VLDL concentrations varied widely among horses in response to withholding feed. Plasma TG and VLDL concentrations remained unaltered in 2 horses. CONCLUSIONS AND CLINICAL RELEVANCE: Withholding feed significantly increases blood lipid concentrations in horses, but individual horses respond differently. Serum NEFA concentrations were increased in all 4 horses denied feed, indicating mobilization of tissue triglyceride stores. Variation in plasma VLDL concentration in response to withholding feed suggests that its metabolism is strongly influenced by other, as yet undetermined, factors in horses. Differences in the plasma VLDL concentrations among horses in response to withholding feed may be used as an indication of susceptibility to the hyperlipemic syndrome of Equidae.