Overexpression of HSP70 in mouse skeletal muscle protects against muscle damage and age‐related muscle dysfunction

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154339/1/fsb2fj030395fje-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154339/2/fsb2fj030395fje.pd

Effect of lifelong overexpression of HSP70 in skeletal muscle on age‐related oxidative stress and adaptation after nondamaging contractile activity

[EN] Skeletal muscle aging is characterized by atrophy, a deficit in specific force generation, increased susceptibility to injury, and incomplete recovery after severe injury. The ability of muscles of old mice to produce heat shock proteins (HSPs) in response to stress is severely diminished. Studies in our laboratory using HSP70 overexpressor mice demonstrated that lifelong overexpression of HSP70 in skeletal muscle provided protection against damage and facilitated successful recovery after damage in muscles of old mice. The mechanisms by which HSP70 provides this protection are unclear. Aging is associated with the accumulation of oxidation products, and it has been proposed that this may play a major role in age-related muscle dysfunction. Muscles of old wild-type (WT) mice demonstrated increased lipid peroxidation, decreased glutathione content, increased catalase and superoxide dismutase (SOD) activities, and an inability to activate nuclear factor (NF)- B after contractions in comparison with adult WT mice. In contrast, levels of lipid peroxidation, glutathione content, and the activities of catalase and SOD in muscles of old HSP70 overexpressor mice were similar to adult mice and these muscles also maintained the ability to activate NF- B after contractions. These data provide an explanation for the preservation of muscle function in old HSP70 overexpressor mice.—Broome, C. S., Kayani, A. C., Palomero, J., Dillmann, W. H., Mestril, R., Jackson, M. J., McArdle, A. Effect of lifelong overexpression of HSP70 in skeletal muscle on age-related oxidative stress and adaptation after nondamaging contractile activity

Cerebral and Extracranial Neurodegeneration are Strongly Coupled in Parkinson’s Disease

In idiopathic Parkinson’s disease (PD), a generalized Lewy body type-degeneration in the brain as well as extracranial organs was identified. It is unclear, whether cerebral and extracranial Lewy body type-degeneration in PD are coupled or not. To address this question, cerebral [123I]FP-CIT SPECT – to quantify cerebral nigrostriatal dopaminergic degeneration – and myocardial [123I]MIBG scintigraphy – to quantify extracranial myocardial sympathetic degeneration – were performed in 95 PD patients and 20 healthy controls. At each Hoehn and Yahr stage separately, myocardial MIBG uptake correlated significantly with striatal FP-CIT uptake. No such correlation was found in the controls. Cerebral and extracranial Lewy body type-degeneration in PD do not develop independently from each other but develop in a strongly coupled manner. Obviously cerebral and extracranial changes are driven by at least similar pathomechanisms. Our findings in controls contradict a physiological correlation between nigrostriatal dopaminergic and myocardial sympathetic function

Role of Myotonic Dystrophy Protein Kinase (DMPK) in Glucose Homeostasis and Muscle Insulin Action

Myotonic dystrophy 1 (DM1) is caused by a CTG expansion in the 3′-unstranslated region of the DMPK gene, which encodes a serine/threonine protein kinase. One of the common clinical features of DM1 patients is insulin resistance, which has been associated with a pathogenic effect of the repeat expansions. Here we show that DMPK itself is a positive modulator of insulin action. DMPK-deficient (dmpk−/−) mice exhibit impaired insulin signaling in muscle tissues but not in adipocytes and liver, tissues in which DMPK is not expressed. Dmpk−/− mice display metabolic derangements such as abnormal glucose tolerance, reduced glucose uptake and impaired insulin-dependent GLUT4 trafficking in muscle. Using DMPK mutants, we show that DMPK is required for a correct intracellular trafficking of insulin and IGF-1 receptors, providing a mechanism to explain the molecular and metabolic phenotype of dmpk−/− mice. Taken together, these findings indicate that reduced DMPK expression may directly influence the onset of insulin-resistance in DM1 patients and point to dmpk as a new candidate gene for susceptibility to type 2-diabetes

Neuronal Na+ Channels Are Integral Components of Pro-Arrhythmic Na+/Ca2+ Signaling Nanodomain That Promotes Cardiac Arrhythmias During β-Adrenergic Stimulation

SummaryAlthough triggered arrhythmias including catecholaminergic polymorphic ventricular tachycardia (CPVT) are often caused by increased levels of circulating catecholamines, the mechanistic link between β-adrenergic receptor (AR) stimulation and the subcellular/molecular arrhythmogenic trigger(s) is unclear. Here, we systematically investigated the subcellular and molecular consequences of β-AR stimulation in the promotion of catecholamine-induced cardiac arrhythmias. Using mouse models of cardiac calsequestrin-associated CPVT, we demonstrate that a subpopulation of Na+ channels, mainly the neuronal Na+ channels (nNav), colocalize with ryanodine receptor 2 (RyR2) and Na+/Ca2+ exchanger (NCX) and are a part of the β-AR-mediated arrhythmogenic process. Specifically, augmented Na+ entry via nNav in the settings of genetic defects within the RyR2 complex and enhanced sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA)-mediated SR Ca2+ refill is both an essential and a necessary factor for arrhythmogenesis. Furthermore, we show that augmentation of Na+ entry involves β-AR–mediated activation of CAMKII, subsequently leading to nNav augmentation. Importantly, selective pharmacological inhibition as well as silencing of Nav1.6 inhibit myocyte arrhythmic potential and prevent arrhythmias in vivo. Taken together, these data suggest that the arrhythmogenic alteration in Na+/Ca2+ handling evidenced ruing β-AR stimulation results, at least in part, from enhanced Na+ influx through nNav. Therefore, selective inhibition of these channels and of Nav1.6 in particular can serve as a potential antiarrhythmic therapy

Profiling quality of care for patients with chronic headache in three different German hospitals – a case study

BACKGROUND: Legal requirements for quality assurance in German rehabilitation hospitals include comparisons of providers. Objective is to describe and to compare outcome quality of care offered by three hospitals providing in-patient rehabilitative treatment exemplified for patients with chronic headache. METHODS: We performed a prospective three center observational study on patients suffering from chronic headache. Patients underwent interventions commonly used according to internal guidelines of the hospitals. Measurements were taken at three points in time (at admission, at discharge and 6 months after discharge). Indicators of outcome quality included pain intensity and frequency of pain, functional ability, depression, quality of life and health related behavior. Analyses of differences amongst the hospitals were adjusted by covariates due to case-mix situation. RESULTS: 306 patients from 3 hospitals were included in statistical analysis. Amongst the hospitals, patients differed significantly in age, education, diagnostic subgroups, beliefs, and with respect to some pain-related baseline values (covariates). Patients in all three hospitals benefited from intervention to a clinically relevant degree. At discharge from hospital, outcome quality differed significantly after adjustment according to case-mix only in terms of patients' global assessment of treatment results. Six months after discharge, the only detectable significant differences were for secondary outcomes like improved coping with stress or increased use of self-help. The profiles for satisfaction with the hospital stay showed clear differences amongst patients. CONCLUSION: The results of this case study do not suggest a definite overall ranking of the three hospitals that were compared, but outcome profiles offer a multilayer platform of reliable information which might facilitate decision making

2004, “Decreased sarcoplasmic reticulum activity in diabeticdb/db mouse heart

Although it is known that insulin-dependent (type 1) diabetes results in depressed contractile performance associated with diminished sarcoendoplasmic reticular Ca 2؉ -ATPase (SERCA2a) activity, findings in insulinresistant (type 2) diabetes suggest a less clear association. The db/db insulin-resistant mouse model exhibits decreased cardiac performance both in situ and in isolated ex vivo working hearts. In this study, contractile performance and calcium transients were measured in Langendorff-perfused hearts and isolated cardiac myocytes. Diabetic (db/db) mouse hearts demonstrated decreased rates of contraction, relaxation, and pressure development. Calcium transients from isolated myocytes revealed significantly lower diastolic and systolic levels of calcium in diabetic hearts. Furthermore, the decay rate of the calcium transient was significantly reduced in diabetic myocytes, suggesting a diminished capacity for cytosolic calcium removal not associated with a change in sodium-calcium exchanger activity. Calcium leakage from the sarcoplasmic reticulum (SR) measured using tetracaine was significantly increased in diabetic myocytes. Western blot analysis indicated only a small decrease in SERCA2a expression in diabetic mice, but a large increase in phospholamban expression. Expression of the ryanodine receptor did not differ between groups. In conclusion, the decreased contractile function observed in the db/db diabetic mouse model appears to be related to decreased calcium handling by the SR. Diabetes 53:3201-3208, 2004 H eart disease is the leading cause of death among diabetic patients. It has been recognized for a number of years that diabetes can impair myocardial performance independent of coronary artery disease or hypertension (1,2). Type 2 (noninsulin-dependent) diabetes is the most prevalent form of this disease, resulting from a combination of insulin resistance (resulting in hyperinsulinemia) and ultimately a failure of pancreatic ␤-cells to maintain adequate insulin secretion to overcome resistance (3,4). The etiology of type 2 diabetes is complex, arising from a mixture of genetic and environmental factors. In contrast, type 1 (insulin-dependent) diabetes is characterized by decreased insulin secretion and is readily reversed by insulin replacement. Although a number of studies have examined the effect of type 1 diabetes on contractile function in the heart, fewer such studies have been performed in type 2 diabetic models. The db/db mouse model of type 2 diabetes was originally isolated from the C57BLK6 strain Ͼ30 years ago (5). Disease development in this strain follows a distinct pattern. Outwardly, the mice are indistinguishable from their nondiabetic littermates until soon after weaning, when they show an accelerated gain in body mass. Initially, insulin secretion increases to overcome insulin resistance in the periphery to prevent hyperglycemia. By age 8 -12 weeks, the maximum extent of hyperinsulinemia is attained; hyperglycemia then develops when the insulin levels are no longer sufficient to counter the insulin resistance (6,7). In the diabetic state, these mice show a diminished capacity for cardiac power output in the isolated working heart preparation (8). This effect is age dependent with the onset of diabetes (9), an observation confirmed in vivo by echocardiography (10). Although this model shows some characteristics similar to type 1 diabetes, including altered metabolic substrate preference (11), it is not known how calcium handling is affected in this model. Alterations in myocyte calcium handling in type 1 diabetes have been well documented (12-14). The type 1 diabetic model is associated with a depression in contractile function underlined primarily by reduced sequestration of calcium into the sarcoplasmic reticulum (SR) as a result of decreased sarcoendoplasmic reticular Ca 2ϩ -ATPase (SERCA) pump activity. The decreased SERCA pump activity is the result of either a decreased expression of SERCA itself or an increase in the prevalence of its inhibitory protein phospholamban (PLN