Fasting plasma lactate as a possible early clinical marker for metabolic disease risk.

BACKGROUND AND AIM: Elevated fasting plasma lactate concentrations are evident in individuals with metabolic diseases. However, it has yet to be determined if these associations exist in a young, healthy population as a possible early marker for metabolic disease risk. The purpose of this study was to determine if indices of the metabolic syndrome are related to plasma lactate concentrations in this population. METHODS: Fifty (29 ± 7 yr) men (n = 19) and women (n = 31) classified as overweight (26.4 ± 1.8 kg/m2) participated in this observational study. Blood pressure and blood metabolites were measured after an overnight fast. Lactate was also measured before and after a three-day eucaloric high-fat (70 %) diet. The homeostatic model assessment for insulin resistance (HOMA-IR) was calculated as a measure of insulin resistance. Visceral adipose tissue mass was determined via dual X-ray absorptiometry. RESULTS: Triglycerides (r = 0.55, p=<0.0001), HOMA-IR (r = 0.53, p=<0.0001), and systolic and diastolic (both, r = 0.36, p = 0.01) blood pressures associated with fasting plasma lactate. No differences in visceral adipose tissue existed between the sexes (p = 0.41); however, the relationship between visceral adipose tissue and lactate existed only in females (r = 0.59, p = 0.02) but not in males (p = 0.53). Fasting lactate and HOMA-IR increased in males (p = 0.01 and p = 0.02, respectively), but not females, following a three-day high-fat diet. CONCLUSION: Indices of the metabolic syndrome associated with fasting plasma lactates in young relatively healthy individuals. Fasting lactate also increased in a sex-specific manner after a three-day high fat diet. Thus, lactate could become a clinical marker for metabolic disease risk.

Greater reliance on glycolysis is associated with lower mitochondrial substrate oxidation and insulin sensitivity in infant myogenic MSCs.

Individuals with insulin resistance and obesity display higher skeletal muscle production of nonoxidized glycolytic products (i.e., lactate), and lower complete mitochondrial substrate oxidation to CO2. These findings have also been observed in individuals without obesity and are associated with an increased risk for metabolic disease. The purpose of this study was to determine if substrate preference is evident at the earliest stage of life (birth) and to provide a clinical blood marker (lactate) that could be indicative of a predisposition for metabolic disease later. We used radiolabeled tracers to assess substrate oxidation and insulin sensitivity of myogenically differentiated mesenchymal stem cells (MSCs), a proxy of infant skeletal muscle tissue, derived from umbilical cords of full-term infants. We found that greater production of nonoxidized glycolytic products (lactate, pyruvate, alanine) is directly proportional to lower substrate oxidation and insulin sensitivity in MSCs. In addition, we found an inverse relationship between the ratio of complete glucose oxidation to CO2 and infant blood lactate at 1 mo of age. Collectively, considering that higher lactate was associated with lower MSC glucose oxidation and has been shown to be implicated with metabolic disease, it may be an early indicator of infant skeletal muscle phenotype.NEW & NOTEWORTHY In infant myogenically differentiated mesenchymal stem cells, greater production of nonoxidized glycolytic products was directly proportional to lower substrate oxidation and insulin resistance. Glucose oxidation was inversely correlated with infant blood lactate. This suggests that innate differences in infant substrate oxidation exist at birth and could be associated with the development of metabolic disease later in life. Clinical assessment of infant blood lactate could be used as an early indicator of skeletal muscle phenotype.

Ockham's razor and the metabolic syndrome.

The broad effects of bariatric/metabolic surgery on virtually every tissue and organ system remain unexplained. Weight loss, although a major factor, does not fully account for the rapid, full, and durable remission of type 2 diabetes, return of islet function, reduction of the prevalence of cancers, increase in gray matter of the brain, and decrease in all-cause mortality. This review supports the thesis that the metabolic syndrome is not a group of separate diseases but rather multiple expressions of a shared defect in the utilization of carbohydrates and lipids. That error is probably caused by a dysmetabolic signal from the foregut, stimulated by food, that limits entry of 2-carbon fragments into the tricarboxylic acid cycle, the accumulation of lactate and, in turn, increases in glucose and insulin. Surgery limits that signal by reducing contact between food and foregut mucosa. Speciation of that signal(s) may offer a new pathway for drug development.

The association between lactate and muscle aerobic substrate oxidation: Is lactate an early marker for metabolic disease in healthy subjects?

Fasting plasma lactate concentrations are elevated in individuals with metabolic disease. The aim of this study was to determine if the variance in fasting lactate concentrations were associated with factors linked with cardiometabolic health even in a young, lean cohort. Young (age 22 ± 0.5; N = 30) lean (BMI (22.4 ± 0.4 kg/m2 ) women were assessed for waist-to-hip ratio, aerobic capacity (VO2 peak), skeletal muscle oxidative capacity (near infrared spectroscopy; fat oxidation from muscle biopsies), and fasting glucose and insulin (HOMA-IR). Subjects had a mean fasting lactate of 0.9 ± 0.1 mmol/L. The rate of deoxygenation of hemoglobin/myoglobin (R2  = .23, p = .03) in resting muscle and skeletal muscle homogenate fatty acid oxidation (R2  = .72, p = .004) were inversely associated with fasting lactate. Likewise, cardiorespiratory fitness (time to exhaustion during the VO2 peak test) was inversely associated with lactate (R2  = .20, p = .05). Lactate concentration was inversely correlated with HDL:LDL (R2  = .57, p = .02) and positively correlated with the waist to hip ratio (R2  = .52, p = .02). Plasma lactate was associated with various indices of cardiometabolic health. Thus, early determination of fasting lactate concentration could become a common biomarker used for identifying individuals at early risk for metabolic diseases.

Oseltamivir-Current Dosing Recommendations Reduce the Therapeutic Benefit in Patients With Mild to Moderate Renal Function and/or Large Body Mass: A Review of the Literature With Recommendations to Optimize Dosing, Including the Use of Therapeutic Drug Monitoring.

PURPOSE: Oseltamivir is indicated for the treatment and prophylaxis of influenza infections. Achieving therapeutic concentrations EARLY in the course of the infection impacts greatly on the magnitude of benefit. Oseltamivir is renally cleared and dose reductions are advised for patients with renal impairment. The purpose of this review was to determine whether these dose reductions facilitate the early attainment of therapeutic concentrations. The review also examined the effect of body mass on the same outcome. METHOD: Oseltamivir is administered as a prodrug and converted to the active carboxylate moiety in the liver. Published articles that included oseltamivir carboxylate (OC) pharmacokinetics in patients with renal impairment and those with large body mass were reviewed. Concentrations of OC achieved in the first 24 hours were compared with those from patients with normal renal function and body mass. RESULTS: Studies that informed dosage regimens for patients with mild to moderately impaired renal function focused on attaining steady-state concentrations similar to those observed in patients with normal renal function. They overlooked the importance of achieving therapeutic concentrations EARLY in the course of the infection. As a result, many patients will not attain therapeutic concentrations until too late in the infection. This is also true for patients with a large body mass. CONCLUSIONS: Current dosing advice for oseltamivir in patients with mild to moderate renal impairment and those with a larger body mass are likely to reduce (or even negate) its efficacy. The first dose should be 75 mg for patients with normal body mass and proportionately larger when body mass is larger. Subsequent doses should be reduced in proportion to the degree of renal impairment. Timely therapeutic drug monitoring can provide invaluable dosing (and other) information to the clinician treating patients with influenza and could improve patient outcomes.

Impaired glucose partitioning in primary myotubes from severely obese women with type 2 diabetes.

The purpose of this study was to determine whether intramyocellular glucose partitioning was altered in primary human myotubes derived from severely obese women with type 2 diabetes. Human skeletal muscle cells were obtained from lean nondiabetic and severely obese Caucasian females with type 2 diabetes [body mass index (BMI): 23.6 ± 2.6 vs. 48.8 ± 1.9 kg/m2, fasting glucose: 86.9 ± 1.6 vs. 135.6 ± 12.0 mg/dL, n = 9/group]. 1-[14C]-Glucose metabolism (glycogen synthesis, glucose oxidation, and nonoxidized glycolysis) and 1- and 2-[14C]-pyruvate oxidation were examined in fully differentiated myotubes under basal and insulin-stimulated conditions. Tricarboxylic acid cycle intermediates were determined via targeted metabolomics. Myotubes derived from severely obese individuals with type 2 diabetes exhibited impaired insulin-mediated glucose partitioning with reduced rates of glycogen synthesis and glucose oxidation and increased rates of nonoxidized glycolytic products, when compared with myotubes derived from the nondiabetic individuals (P < 0.05). Both 1- and 2-[14C]-pyruvate oxidation rates were significantly blunted in myotubes from severely obese women with type 2 diabetes compared with myotubes from the nondiabetic controls. Lastly, concentrations of tricarboxylic acid cycle intermediates, namely, citrate (P < 0.05), cis-aconitic acid (P = 0.07), and α-ketoglutarate (P < 0.05), were lower in myotubes from severely obese women with type 2 diabetes. These data suggest that intramyocellular insulin-mediated glucose partitioning is intrinsically altered in the skeletal muscle of severely obese women with type 2 diabetes in a manner that favors the production of glycolytic end products. Defects in pyruvate dehydrogenase and tricarboxylic acid cycle may be responsible for this metabolic derangement associated with type 2 diabetes.

Plasma lactate as a marker of metabolic health: Implications of elevated lactate for impairment of aerobic metabolism in the metabolic syndrome.

BACKGROUND: Fasting lactate is elevated in metabolic diseases and could possibly be predictive of the risk of developing the metabolic syndrome. METHODS: Plasma samples were analyzed for fasting lactate to compare lean subjects, nondiabetic subjects with severe obesity, and metabolically impaired subjects. Subjects with severe obesity were studied 1 week before and 1 week to 9 months after gastric bypass surgery. Subjects with components of the metabolic syndrome were studied before and after 6 months of an exercise intervention. RESULTS: Metabolically impaired subjects had higher fasting lactate concentrations (P < .0001) and respond to a glucose or insulin challenge with higher lactates than non-obese subjects (P < .004). Lactate was significantly reduced a week after gastric bypass surgery (P < .05) and further reduced 1 to 9 months after surgery (0.95 ± 0.04 mM in non-obese, 1.26 ± 0.12 mM in subjects with severe obesity, and 0.68 ± 0.03 mM 1-3 months after gastric bypass). Six months of chronic exercise resulted in a 16% reduction (P = .028) in fasting lactate. CONCLUSION: Fasting plasma lactate was elevated in obese subjects with the metabolic syndrome compared with healthy lean individuals. Lactate was reduced by exercise and bariatric surgery, interventions that improve metabolic health and risk for subsequent disease. The results of this study and those previously published by our research group suggest that elevated lactate may be caused by an impairment in aerobic metabolism and may offer a metric assessing the severity of the metabolic syndrome.

Ceftazidime stability and pyridine toxicity during continuous i.v. infusion.

PURPOSE: This article reviews the literature concerning ceftazidime stability and potential for toxicity from pyridine (a degradation product) in the light of decades of apparent safe use of this antibiotic when given by continuous i.v. infusion but recent changes in regulatory body/manufacturer advise a need to change infusion devices more frequently. SUMMARY: In the outpatient setting, ceftazidime is ideally administered by continuous i.v. infusion because of its short half-life and lack of post-antibiotic effect. While continuous i.v. infusion provides the optimal pharmacokinetic/pharmacodynamic profile, the frequency with which infusion devices need to be changed is critical to the practicality in the outpatient setting, especially where trained staff are required to visit the patient in their home to change the device. The rate of ceftazidime degradation (and pyridine formation) is temperature, concentration, and solvent dependent. By using the lowest effective dose (guided by pathogen minimum inhibitory concentration [MIC] so as to achieve a blood concentration ≥ 4 × MIC over the whole dosage interval), keeping ceftazidime concentration ≤ 3%, using 0.9% sodium chloride injection as diluent and maintaining temperature between 15-25°C when connected to the patient, the amount of pyridine formed over a 24-hour period can be minimized and toxicity prevented. When pathogen MIC dictates that > 6 g ceftazidime/day is required, alternative antibiotics should be considered and/or greater attention paid to temperature and concentration of the infusion solution. CONCLUSION: Ceftazidime can be used safely and effectively via continuous i.v. infusion in the outpatient setting with once-daily changes of infusion device provided the concentration and temperature of the infusion solution is controlled. In this way, more frequent changes of infusion device (that increase the risk of blood-borne infection and reduce the practicality of continuous i.v. infusion in the home) can be avoided.

Altered tricarboxylic acid cycle flux in primary myotubes from severely obese humans.

BACKGROUND/OBJECTIVE: The partitioning of glucose toward glycolytic end products rather than glucose oxidation and glycogen storage is evident in skeletal muscle with severe obesity and type 2 diabetes. The purpose of the present study was to determine the possible mechanism by which severe obesity alters insulin-mediated glucose partitioning in human skeletal muscle. SUBJECTS/METHODS: Primary human skeletal muscle cells (HSkMC) were isolated from lean (BMI = 23.6 ± 2.6 kg/m2, n = 9) and severely obese (BMI = 48.8 ± 1.9 kg/m2, n = 8) female subjects. Glucose oxidation, glycogen synthesis, non-oxidized glycolysis, pyruvate oxidation, and targeted TCA cycle metabolomics were examined in differentiated myotubes under basal and insulin-stimulated conditions. RESULTS: Myotubes derived from severely obese subjects exhibited attenuated response of glycogen synthesis (20.3%; 95% CI [4.7, 28.8]; P = 0.017) and glucose oxidation (5.6%; 95% CI [0.3, 8.6]; P = 0.046) with a concomitant greater increase (23.8%; 95% CI [5.7, 47.8]; P = 0.004) in non-oxidized glycolytic end products with insulin stimulation in comparison to the lean group (34.2% [24.9, 45.1]; 13.1% [8.6, 16.4], and 2.9% [-4.1, 12.2], respectively). These obesity-related alterations in glucose partitioning appeared to be linked with reduced TCA cycle flux, as 2-[14C]-pyruvate oxidation (358.4 pmol/mg protein/min [303.7, 432.9] vs. lean 439.2 pmol/mg protein/min [393.6, 463.1]; P = 0.013) along with several TCA cycle intermediates, were suppressed in the skeletal muscle of severely obese individuals. CONCLUSIONS: These data suggest that with severe obesity the partitioning of glucose toward anaerobic glycolysis in response to insulin is a resilient characteristic of human skeletal muscle. This altered glucose partitioning appeared to be due, at least in part, to a reduction in TCA cycle flux.

Early alterations in blood and brain RANTES and MCP-1 expression and the effect of exercise frequency in the 3xTg-AD mouse model of Alzheimer's disease.

Exercise has been shown to protect against cognitive decline and Alzheimer's disease (AD) progression, however the dose of exercise required to protect against AD is unknown. Recent studies show that the pathological processes leading to AD cause characteristic alterations in blood and brain inflammatory proteins that are associated with the progression of AD, suggesting that these markers could be used to diagnosis and monitor disease progression. The purpose of this study was to determine the impact of exercise frequency on AD blood chemokine profiles, and correlate these findings with chemokine brain expression changes in the triple transgenic AD (3xTg-AD) mouse model. Three month old 3xTg-AD mice were subjected to 12 weeks of moderate intensity wheel running at a frequency of either 1×/week or 3×/week. Blood and cortical tissue were analyzed for expression of monocyte chemotactic protein-1 (MCP-1) and regulated and normal T cell expressed and secreted (RANTES). Alterations in blood RANTES and MCP-1 expression were evident at 3 and 6 month old animals compared to WT animals. Three times per week exercise but not 1×/week exercise was effective at reversing serum and brain RANTES and MCP-1 expression to the levels of WT controls, revealing a dose dependent response to exercise. Analysis of these chemokines showed a strong negative correlation between blood and brain expression of RANTES. The results indicate that alterations in serum and brain inflammatory chemokines are evident as early signs of Alzheimer's disease pathology and that higher frequency exercise was necessary to restore blood and brain inflammatory expression levels in this AD mouse model.

Drugs potentially affecting the extent of airways reversibility on pulmonary function testing are frequently consumed despite guidelines.

BACKGROUND: The increase in forced expiratory volume in one second (FEV1) effected by a bronchodilator is routinely assessed when patients undertake pulmonary function testing (PFT). Several drug classes can theoretically affect the magnitude of the increase in FEV1. Withholding periods are advised for many but not all such drugs. Anecdotally, many subjects presenting for PFT are found to have taken drugs that might affect the test. We did an audit of patients presenting for PFT to assess the frequency with which FEV1 reversibility might be affected by drugs. METHODS: One hundred subjects presenting to the laboratory for PFT were questioned about recent drug consumption by an independent pharmacy intern. Reversibility of FEV1 was assumed to have been affected if drugs of interest were consumed within defined withholding periods or two half-lives for drugs without such data. RESULTS: Sixty-three subjects were prescribed drugs likely to affect FEV1 reversibility. Thirty-six subjects consumed at least one such drug within the withholding period. Half (18) of these patients consumed ß-blockers with or without ß-agonists. Sixty-five subjects did not recall receiving any advice about withholding drugs prior to the test and only 10 recalled receiving advice from their clinician or pulmonary function technician. CONCLUSION: Subjects presenting for PFT are infrequently advised to withhold drugs that may affect FEV1 reversibility, and consequently, often take such drugs close to the time of the test. Therefore, it is likely that the increase in FEV1 is frequently affected by interference from drugs and this might impact on diagnosis and/or treatment options.

False-positive ethanol blood concentrations leading to clinical confusion on Christmas Day.

A case of altered consciousness in which ethanol ingestion was one of the differential diagnoses is described. Three separate blood samples were conveyed to the hospital biochemistry laboratory and each returned a positive value when assayed via an indirect, enzymatic method. The family strongly denied alcohol ingestion and hence, a few days later, the samples were conveyed to an external laboratory using a 'specific', chromatographic method. These samples were all reported as negative for ethanol. Alternative causes of altered consciousness were restricted by the false-positive ethanol laboratory results.

Sarcopenia--mechanisms and treatments.

BACKGROUND: Sarcopenia is a consequence of aging. This atrophic event is responsible for decrease in strength and associated functional deficits seen in the aging adult. PURPOSE: This paper reviews: (1) the mechanisms contributing to sarcopenia, (2) the impact of age-related changes in muscle composition on 3 processes integral to muscle function, (3) the efficacy of pharmaceuticals and over-the-counter nutritional supplements in the management of sarcopenia, (4) experimental use of pharmaceutical regulation of myostatin to increase muscle mass and strength in animal models, and (5) efficacy of resistance training as a means of maintaining or recovering muscle mass and strength. METHODS: PubMed was searched for relevant research articles using the following descriptors: sarcopenia, aging, muscle mass, muscle performance, muscle strength, myostatin, testosterone, growth hormone, dehydroepiandrosterone, hormone replacement, nutrition, resistance training, and endurance training. RESULTS: Sarcopenia is mediated by multiple mechanisms, including alpha-motor neuron death, altered hormone concentrations, increased inflammation, and altered nutritional status. Age-related changes within muscle likely affect processes integral to muscle function. These changes negatively influence muscle performance directly or by contributing to sarcopenia. Pharmaceutical or supplement interventions to treat sarcopenia have not proved encouraging to date, either lacking or providing limited efficacy, along with the potential for negative health consequences. In contrast, resistance training has proven safe and highly effective for increasing muscle mass and strength in aging adults. CONCLUSION: Sarcopenia is a multifactorial consequence of aging that will affect many adults. Resistance training is the most effective and safe intervention to attenuate or recover some of the loss of muscle mass and strength that accompanies aging.

Long-term exercise training in overweight adolescents improves plasma peptide YY and resistin.

The objective of this study was to investigate the effect of long-term exercise training on concentrations of five hormones related to appetite and insulin resistance in overweight adolescents. In addition, we were interested in the relationships of these hormones with each other and with anthropometric and/or cardiovascular disease marker changes. Participants were >or=the 85th percentile for BMI for age and sex and participated in an 8-month supervised aerobic training program. Anthropometrics, cardiovascular fitness assessment, and fasting blood samples were taken pre- and post-training. Glucose, insulin, total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, leptin, active ghrelin, total peptide YY (PYY), adiponectin, and resistin concentrations were measured. The participants increased their time to exhaustion on an incremental treadmill test and decreased both percent body fat and blood triglyceride concentrations. Total PYY concentration increased and resistin concentration decreased after long-term exercise training, which are favorable outcomes. Leptin concentrations were related to weight, percent body fat, waist circumference, and triglyceride concentrations pre- and post-training. The changes in resistin concentrations were related to the changes in triglyceride concentrations. We conclude that long-term exercise training has beneficial effects for overweight adolescents with respect to PYY and resistin, hormones related to appetite and insulin sensitivity.

Discordant results from "real-world" patient samples assayed for digoxin.

BACKGROUND: Digoxin has a narrow therapeutic index and is primarily renally eliminated. To optimize dosing of digoxin, therapeutic drug monitoring has been important since assays became available in the 1970s. Immunoassays are not specific, and cross-reactivity with endogenous and exogenous compounds has been reported for more than 20 years. Interassay concordance has not been investigated in recent years in "real-world" patient samples. OBJECTIVE: To identify whether different digoxin immunoassays produce clinically different results in real-world situations, estimate the frequency of discordance, and determine whether an equation-based estimate compares well with digoxin immunoassays. METHODS: Plasma samples were sent to 2 accredited laboratories simultaneously and the digoxin results were compared. Results of immunoassays conducted using the Cedia DRI Digoxin Assay and the DGNA Digoxin Assay were compared with an equation-based estimate of plasma digoxin concentration. RESULTS: Thirty-six digoxin samples were assayed; in 39% of these, digoxin concentrations were discordant and different dosage adjustments would have followed. The presence of digoxin-like immunoreactive substances may explain some of this discordance. The mean of the equation-based result was similar to the immunoassay results, but marked variability was evident. The DGNA assay produced higher results on 24 samples; 9 higher values occurred with the DRI method. CONCLUSIONS: Commercial digoxin immunoassays frequently produce clinically significant discordant results. The equation-based estimate does not appear to be an acceptable alternative to therapeutic drug monitoring. Immunoassay manufacturers should be required to improve assay performance by including real-world blood samples in development and clinicians should consider digoxin assay results warily.

Measuring the unbound concentration fails to resolve analytic interferences in digoxin immunoassays.

Therapeutic drug monitoring of digoxin is well established in the clinical management of cardiac patients treated with the drug. Recently, target concentrations have been revised in patients with congestive heart failure to 0.5 to 0.8 microg/L, challenging the sensitivity limits of most immunoassays. These widely used methods are often criticized, particularly on specificity grounds resulting from interference from exogenous and endogenous sources. One solution to remove higher molecular weight interference has been to ultrafilter plasma samples before assaying. The present study included 261 patient digoxin samples and compared two commercial ultrafiltration devices (Centrifree and Micrcon) that share the same separation membrane (YM-30). The results showed widely discordant apparent unbound digoxin concentrations in the ultrafiltrate from these devices with a Deming regression line of Centrifree = 1.31 x Micrcon + 0.042 (95% confidence interval for slope of 1.237 to 1.391) and apparent unbound fractions ranging from 15% to 610% of the unfiltered plasma digoxin concentrations, suggesting that ultrafiltration did not resolve such interference issues. The concept of measuring lower unbound digoxin concentrations as a result of lower therapeutic range for total (bound plus unbound) digoxin will also render most immunoassays insensitive and inappropriately calibrated. There is a strong imperative to review digoxin monitoring practices in the light of current clinical imperatives for both specificity and sensitivity reasons.

Loss of the calmodulin-dependent inhibition of the RyR1 calcium release channel upon oxidation of methionines in calmodulin.

The oxidation of methionines in calmodulin (CaM) can affect the activity of calcium pumps and channels to modulate the amplitude and duration of calcium signals. We have therefore investigated the possible oxidation of CaM in skeletal muscle and its effect on the CaM-dependent regulation of the RyR1 calcium release channel. Taking advantage of characteristic reductions in electrophoretic mobility determined by SDS-PAGE, we find that approximately two methionines are oxidized in CaM from skeletal muscle. The functional effect of CaM oxidation on the open probability of the RyR1 calcium release channel was assessed through measurements of [3H]ryanodine binding using a heavy sarcoplasmic reticulum preparation enriched in RyR1. There is a biphasic regulation of RyR1 by unoxidized CaM, in which calcium-activated CaM acts to enhance the calcium sensitivity of channel closure, while apo-CaM functions to enhance channel activity at resting calcium levels. We find that physiological levels of CaM oxidation preferentially weaken the CaM-dependent inhibition of the RyR1 calcium release channel observed at activating micromolar levels of calcium. In contrast, the oxidation of CaM resulted in minimal functional changes in the CaM-dependent activation of RyR1 at resting nanomolar calcium levels. Oxidation does not significantly affect the high-affinity binding of calcium-activated CaM to the CaM-binding sequence of RyR1; rather, methionine oxidation disrupts interdomain interactions between the opposing domains of CaM in complex with the CaM-binding sequence of RyR1 that normally function as part of a conformational switch associated with RyR1 inhibition. These results suggest that the oxidation of CaM can contribute to observed elevations in intracellular calcium levels in response to conditions of oxidative stress observed during biological aging. We suggest that the sensitivity of RyR1 channel activity to CaM oxidation may function as part of an adaptive cellular response that enhances the duration of calcium transients to promote enhanced contractility.