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Background
Previous data from a 2-year randomized controlled trial (CRAD001ADE12) indicated that mammalian target of rapamycin (mTOR) inhibition by everolimus slowed cyst growth in patients with autosomal-dominant polycystic kidney disease (ADPKD). During the trial, we noted body weight loss in some patients, particularly in women. We hypothesized that everolimus causes body weight reduction by reduced food intake and/or metabolic changes, which could lead to cachexia.
Methods
Within a sub-analysis of the CRAD001ADE12 trial, body weight course was investigated regarding sex-specific differences in 433 adult ADPKD patients (everolimus, n = 215; placebo, n = 218). One hundred four out of 111 patients who participated in the clinical trial centre in Berlin were evaluated under everolimus/placebo therapy (on drug: everolimus, n = 48; placebo, n = 56) and after therapy (off drug: everolimus, n = 15; placebo, n = 18). Eating habits and nutrient/caloric intake were evaluated by validated questionnaires. Systemic and local metabolism was evaluated in four patients after an oral glucose load (OGL) by using calorimetry and adipose/muscle tissue microdialysis.
Results
Within the 2-year CRAD001ADE12 trial, a significant body weight loss was observed in female patients on everolimus versus placebo (P = 0.0029). Data of the Berlin Cohort revealed that weight loss was greater in women on everolimus versus men (P < 0.01). After 9 months, women and men had lost 2.6 ± 3.8 and 0.8 ± 1.5 kg (P < 0.05) in body weight, respectively, and after 21 months, they had lost 4.1 ± 6.6 and 1.0 ± 3.3 kg (P < 0.05), respectively. On everolimus, caloric intake was significantly lower in women versus men (1510 ± 128 vs. 2264 ± 216 kcal/day, P < 0.05), caused mainly by a lower fat and protein intake in women versus men. Cognitive restraints, disinhibition and hunger remained unchanged. In a subgroup of patients resting metabolic rate was unchanged whereas OGL-induced thermogenesis was reduced (7 ± 2 vs. 11 ± 2 kcal, P < 0.05). Fasting and OGL-induced fat oxidation was increased (P < 0.05) on versus off everolimus. In adipose tissue, fasting lipolytic activity was increased, but lipolytic activity was inhibited similarly after the OGL on versus off everolimus, respectively. In skeletal muscle, postprandial glucose uptake and aerobic glycolysis was reduced in patients on everolimus.
Conclusions
mTOR inhibition by everolimus induces body weight reduction, specifically in female patients. This effect is possibly caused by a centrally mediated reduced food (fat and protein) intake and by centrally/peripherally mediated increased fat oxidation (systemic) and mobilization (adipose tissue). Glucose uptake and oxidation might be reduced in skeletal muscle. This could lead to cachexia and, possibly, muscle wasting. Therefore, our results have important implications for patients recieving immune-suppressive mTOR inhibition therapy.
Background
Sepsis-induced intensive care unit-acquired weakness (ICUAW) features profound muscle atrophy and attenuated muscle regeneration related to malfunctioning satellite cells. Transforming growth factor beta (TGF-β) is involved in both processes. We uncovered an increased expression of the TGF-β receptor II (TβRII)-inhibitor SPRY domain-containing and SOCS-box protein 1 (SPSB1) in skeletal muscle of septic mice. We hypothesized that SPSB1-mediated inhibition of TβRII signalling impairs myogenic differentiation in response to inflammation.
Methods
We performed gene expression analyses in skeletal muscle of cecal ligation and puncture- (CLP) and sham-operated mice, as well as vastus lateralis of critically ill and control patients. Pro-inflammatory cytokines and specific pathway inhibitors were used to quantitate Spsb1 expression in myocytes. Retroviral expression plasmids were used to investigate the effects of SPSB1 on TGF-β/TβRII signalling and myogenesis in primary and immortalized myoblasts and differentiated myotubes. For mechanistical analyses we used coimmunoprecipitation, ubiquitination, protein half-life, and protein synthesis assays. Differentiation and fusion indices were determined by immunocytochemistry, and differentiation factors were quantified by qRT-PCR and Western blot analyses.
Results
SPSB1 expression was increased in skeletal muscle of ICUAW patients and septic mice. Tumour necrosis factor (TNF), interleukin-1β (IL-1β), and IL-6 increased the Spsb1 expression in C2C12 myotubes. TNF- and IL-1β-induced Spsb1 expression was mediated by NF-κB, whereas IL-6 increased the Spsb1 expression via the glycoprotein 130/JAK2/STAT3 pathway. All cytokines reduced myogenic differentiation. SPSB1 avidly interacted with TβRII, resulting in TβRII ubiquitination and destabilization. SPSB1 impaired TβRII-Akt-Myogenin signalling and diminished protein synthesis in myocytes. Overexpression of SPSB1 decreased the expression of early (Myog, Mymk, Mymx) and late (Myh1, 3, 7) differentiation-markers. As a result, myoblast fusion and myogenic differentiation were impaired. These effects were mediated by the SPRY- and SOCS-box domains of SPSB1. Co-expression of SPSB1 with Akt or Myogenin reversed the inhibitory effects of SPSB1 on protein synthesis and myogenic differentiation. Downregulation of Spsb1 by AAV9-mediated shRNA attenuated muscle weight loss and atrophy gene expression in skeletal muscle of septic mice.
Conclusions
Inflammatory cytokines via their respective signalling pathways cause an increase in SPSB1 expression in myocytes and attenuate myogenic differentiation. SPSB1-mediated inhibition of TβRII-Akt-Myogenin signalling and protein synthesis contributes to a disturbed myocyte homeostasis and myogenic differentiation that occurs during inflammation.
Post-COVID-19 syndrome (PCS) has been described as ‘the pandemic after the pandemic’ with more than 65 million people worldwide being affected. The enormous range of symptoms makes both diagnosis complex and treatment difficult. In a post-COVID rehabilitation outpatient clinic, 184 patients, mostly non-hospitalized, received a comprehensive, interdisciplinary diagnostic assessment with fixed follow-up appointments. At baseline, three in four patients reported more than 10 symptoms, the most frequent symptoms were fatigue (84.9%), decreased physical capacity (83.0%), tiredness (81.1%), poor concentration (73.6%), sleeping problems (66.7%) and shortness of breath (67.3%). Abnormalities were found in the mean values of scores for fatigue (FAS = 34.3), cognition (MoCA = 25.5), psychological alterations (anxiety, depression, post-traumatic stress disorder), limitation of lung function (CAT) and severity scores for PCS (PCFS, MCRS). Clinical abnormalities were found in elevated values of heart rate, breathing rate at rest, blood pressure and NT-proBNP levels. As the frequency of the described symptoms decreases only slowly but most often significantly over the course, it is important to monitor the patients over a longer period of time. Many of them suffer from an immense symptom burden, often without pre-existing clinical correlates. Our results show a clear association with objectifiable assessments and tests as well as pronounced symptoms.