Glucocorticoid intermittence coordinates rescue of energy and mass in aging-related sarcopenia through the myocyte-autonomous PGC1alpha-Lipin1 transactivation.

Sarcopenia burdens the elderly population through loss of muscle energy and mass, yet treatments to functionally rescue both parameters are missing. The glucocorticoid prednisone remodels muscle metabolism based on frequency of intake, but its mechanisms in sarcopenia are unknown. We found that once-weekly intermittent prednisone rescued muscle quality in aged 24-month-old mice to levels comparable to young 4-month-old mice. We discovered an age- and sex-independent glucocorticoid receptor transactivation program in muscle encompassing PGC1alpha and its co-factor Lipin1. Treatment coordinately improved mitochondrial abundance through isoform 1 and muscle mass through isoform 4 of the myocyte-specific PGC1alpha, which was required for the treatment-driven increase in carbon shuttling from glucose oxidation to amino acid biogenesis. We also probed the myocyte-specific Lipin1 as non-redundant factor coaxing PGC1alpha upregulation to the stimulation of both oxidative and anabolic capacities. Our study unveils an aging-resistant druggable program in myocytes to coordinately rescue energy and mass in sarcopenia.

Measuring the impact of steroid therapy on health-related quality of life in patients with rheumatic diseases: international development of a glucocorticoid treatment-specific patient-reported outcome measure.

OBJECTIVES: Glucocorticoids (GCs) ('steroids') are used to treat rheumatic diseases but adverse effects are common. We aimed to explore the impact of GC therapy on health-related quality of life (HRQoL), to inform the development of a treatment-specific patient-reported outcome measure (PROM) for use in clinical trials and practice. METHODS: Semi-structured qualitative interviews were conducted with patients from the UK, USA and Australia, treated for a rheumatic condition with GCs in the last 2 years. Purposive sampling was used to select participants with a range of demographic and disease features. An initial conceptual framework informed interview prompts and cues. Interviews elicited GC-related physical and psychological symptoms and salient aspects of HRQoL in relation to GC therapy. Interview data were analysed inductively to develop initial individual themes and domains. Candidate questionnaire items were developed and refined. RESULTS: Sixty semi-structured qualitative interviews were conducted (UK n = 34, USA n = 10, Australia n = 16). The mean age was 58 years; 39/60 were female; and 18 rheumatic diseases were represented. Some 126 individual themes were identified and organized into six domains: physical symptoms; psychological symptoms; psychological impact of steroids; impact of steroids on participation; impact of steroids on relationships; and benefits of steroids. Candidate questionnaire items were tested and refined by piloting with patient research partners, iterative rounds of cognitive interviews and linguistic translatability assessment, informing a draft questionnaire. CONCLUSION: We describe an international qualitative study to develop candidate items for a treatment-specific PROM for patients with rheumatic diseases. A future survey will enable the validation of a final version of the PROM.

Effects of Glucocorticoids in Murine Models of Duchenne and Limb-Girdle Muscular Dystrophy.

In vivo testing of glucocorticoid steroids in dystrophic mice offers important insights in benefits and risks of those drugs in the pathological context of muscular dystrophy. Frequency of dosing changes the spectrum of glucocorticoid effects on muscle and metabolic homeostasis. Here, we describe a combination of non-invasive and invasive methods to quantitatively discriminate the specific effects of intermittent (once-weekly) versus mainstay (once-daily) regimens on muscle fibrosis, muscle function, and metabolic homeostasis in murine models of Duchenne and limb-girdle muscular dystrophies.

Impact of circadian time of dosing on cardiomyocyte-autonomous effects of glucocorticoids.

OBJECTIVE: Mitochondrial capacity is critical to adapt the high energy demand of the heart to circadian oscillations and diseased states. Glucocorticoids regulate the circadian cycle of energy metabolism, but little is known about how circadian timing of exogenous glucocorticoid dosing directly regulates heart metabolism through cardiomyocyte-autonomous mechanisms. While chronic once-daily intake of glucocorticoids promotes metabolic stress and heart failure, we recently discovered that intermittent once-weekly dosing of exogenous glucocorticoids promoted muscle metabolism in normal and obese skeletal muscle. However, the effects of glucocorticoid intermittence on heart metabolism and heart failure remain unknown. Here we investigated the extent to which circadian time of dosing regulates the effects of the glucocorticoid prednisone in heart metabolism and function in conditions of single pulse or chronic intermittent dosing. METHODS AND RESULTS: In WT mice, we found that prednisone improved cardiac content of NAD+ and ATP with light-phase dosing (ZT0), while the effects were blocked by dark-phase dosing (ZT12). The drug effects on mitochondrial function were cardiomyocyte-autonomous, as shown by inducible cardiomyocyte-restricted glucocorticoid receptor (GR) ablation, and depended on an intact cardiomyocyte clock, as shown by inducible cardiomyocyte-restricted ablation of Brain and Muscle ARNT-like 1 (BMAL1). Conjugating time-of-dosing with chronic intermittence, we found that once-weekly prednisone improved metabolism and function in heart after myocardial injury dependent on circadian time of intake, i.e. with light-phase but not dark-phase dosing. CONCLUSIONS: Our study identifies cardiac-autonomous mechanisms through which circadian-specific intermittent dosing reconverts glucocorticoid drugs to metabolic boosters for the heart.

Mechanisms and Clinical Applications of Glucocorticoid Steroids in Muscular Dystrophy.

Glucocorticoid steroids are widely used as immunomodulatory agents in acute and chronic conditions. Glucocorticoid steroids such as prednisone and deflazacort are recommended for treating Duchenne Muscular Dystrophy where their use prolongs ambulation and life expectancy. Despite this benefit, glucocorticoid use in Duchenne Muscular Dystrophy is also associated with significant adverse consequences including adrenal suppression, growth impairment, poor bone health and metabolic syndrome. For other forms of muscular dystrophy like the limb girdle dystrophies, glucocorticoids are not typically used. Here we review the experimental evidence supporting multiple mechanisms of glucocorticoid action in dystrophic muscle including their role in dampening inflammation and myofiber injury. We also discuss alternative dosing strategies as well as novel steroid agents that are in development and testing, with the goal to reduce adverse consequences of prolonged glucocorticoid exposure while maximizing beneficial outcomes.

Value of glucocorticoid steroids in the treatment of patients with severe community-acquired pneumonia complicated with septic shock / 中华危重病急救医学

Objective To discuss the value of glucocorticoid steroids (GCs) in the treatment of patients with severe community-acquired pneumonia (SCAP) complicated with septic shock.Methods A prospectively controlled randomized trial was conducted.Fifty-eight SCAP patients complicated with septic shock admitted to emergency intensive care unit (ICU) of China-Japan Friendship Hospital from May 2014 to February 2016 were enrolled.The patients were randomly divided into conventional treatment group (n =29) and GCs group (n =29).Fluid resuscitation,vasopressors,mechanical ventilation if needed,antibiotics and other general treatment including symptomatic treatment and eliminating phlegm were given to patients in both groups.Beside the treatment mentioned above,80 mg methylprednisolone once a day for 7 days was added to patients in GCs group.The changes in oxygenation index (PaO2/FiO2) and C-reactive protein (CRP) at 1,4,8 days after treatment as well as the imaging improvement in both groups were observed.Discharge or death was set as a cut-off point,the average time of temperature controlling,duration of mechanical ventilation,time of vasopressors usage and 28-day mortality were observed.The incidence of hyperglycemia,infection and hemorrhage of digestive tract were observed.Results There were no statistically differences in gender,age and body mass between the two groups,indicating that baseline data for the two groups were balanced.PaO2/FiO2 after treatment in the two groups was gradually increased,and it was significantly higher at 8 days after treatment in GCs group than that of conventional treatment group [mmHg (1 mmHg =0.133 kPa):426.46 ± 86.97 vs.363.00 ± 83.96,P ＜ 0.05].CRP after treatment in the two groups was gradually decreased,and it was significantly lower at 4 days and 8 days after treatment in GCs group than that of conventional treatment group (mg/L:95.78 ± 47.38 vs.124.72 ± 51.01,57.60 ± 47.44 vs.88.85 ± 48.18,both P ＜ 0.05).Radiographic imaging improved rate at 4 days and 8 days after treatment in GCs group was significantly higher than that of conventional treatment group (55.2％ vs.27.6％,75.9％ vs.51.7％,both P ＜ 0.05),and average time of temperature controlling (days:3.94 ± 2.39 vs.7.22 ± 3.11),time of vasopressors usage (hours:13.64 ± 6.47 vs.28.34 ± 12.56),and the average hospitalization days (days:28.50 ± 8.61 vs.36.21 ± 15.26)in GCs group were significantly shorter than those of conventional treatment group (all P ＜ 0.01).There was no significant difference in duration of mechanical ventilation between GCs group and conventional treatment group (days:13.39 ± 2.62 vs.16.16 ± 5.85,P ＞ 0.05).28-day mortality of the two groups was 10.3％ equally (P ＞ 0.05).No significant differences in the incidences of hyperglycemia (10.3％ vs.6.9％),infection (51.7％ vs.55.2％) and gastrointestinal bleeding (3.4％ vs.0) were found between GCs group and conventional treatment group (all P ＞ 0.05),indicating that glucocorticoid steroids could not increase the common side effects.Conclusion GCs is an important adjuvant treatment of patients with SCAP complicated with septic shock.