Walking exercise alters protein digestion, amino acid absorption, and whole body protein kinetics in older adults with and without COPD

Purpose: Gut symptoms and markers of gut dysfunction have been observed in patients with Chronic Obstructive Pulmonary disease (COPD). It remains unclear whether walking exercise induces disturbances in protein digestion and amino acid absorption and whole body protein kinetics in these subjects due to exercise induced hypoxia. Methods: Sixteen clinically stable patients with moderate to very severe COPD and 12 age matched control subjects completed the study. Protein digestion and amino acid absorption and whole body protein kinetics, in the postabsorptive state, were measured via a continuous infusion of stable tracers in combination with orally administered tracer sips during 20 minutes of walking exercise and up to 4 hours post-exercise. COPD patients completed one study day, walking at maximal speed, while healthy subjects completed two, one matched to the speed of a COPD patient and one walking at maximal speed. Results: The COPD patients tolerated 20 minutes of vigorous intensity walking despite elevated heart rate (P<0.001) and substantial desaturation (P<0.001). Relative to rest, protein digestion was increased during recovery from exercise (P<0.05) while amino acid absorption was reduced during (P<0.0001) and immediately after exercise (P<0.001). Whole body protein breakdown was reduced within 20 minutes after exercise (P<0.05) and stayed suppressed for four hours (P<0.0001). Whole body net protein breakdown was elevated for four hours post-exercise (P<0.001). Conclusion: Our data showed that 20 minutes of walking exercise is sufficient to cause substantial perturbations in gut function in older adults and COPD patients with hypoxia as a potential underlying factor.

Model Based Approach to Evaluate Isatuximab Monthly Dosing Regimen in Relapsed/Refractory Multiple Myeloma Patients

Background: Isatuximab (Isa) is a CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement (Moreno, Clin Cancer Res, 2019). The addition of Isa to pomalidomide (P) and dexamethasone (d) was associated with a significant and clinically meaningful benefit in progression-free survival (PFS) in heavily pre-treated patients with relapsed/refractory multiple myeloma (RRMM) (ICARIA-MM, NCT02514668) (Attal, Lancet, 2019). Isa, in combination with Pd, is approved in the United States, the European Union, Canada, Australia, Switzerland, and Japan for the treatment of adult patients with RRMM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. Aim: The objectives were to characterize the relationship between serum M-protein kinetics and PFS in RRMM using data from the Phase 3 ICARIA-MM study and to simulate expected longitudinal serum M-protein and PFS when switching to a hypothetical monthly dosing regimen after 6 months. Methods: A joint model of serum M-protein dynamics and PFS was developed using data from 256 evaluable ICARIA-MM patients. Patients received Isa intravenously at 10 mg/kg once weekly (QW) for 4 weeks, then every other week (Q2W) for 28-day cycles in combination with standard Pd (Isa-Pd) or Pd alone in the control arm. A tumor growth inhibition model was used to describe the serum M-protein kinetics under treatment effects of Isa-Pd or Pd alone, in which Isa exposure was predicted using individual PK parameters obtained from the population PK analysis (Fau, Population Approach Group in Europe, 2019) and Pd exposure was predicted from K-PD model using dosing history. Trial simulations were then performed using individual PK/PD parameters of ICARIA-MM patients to evaluate whether efficacy is maintained after switching to a monthly dosing regimen. Results: The joint model identified the instantaneous changes (slope) in serum M-protein as the best on-treatment predictor for PFS and also identified baseline patient characteristics impacting serum M-protein kinetics (serum albumin and serum β2 microglobulin on the baseline serum M-protein levels and the non-IgG type on the serum M-protein growth rate, the serum M-protein slope), and PFS (presence of plasmacytomas). Non-IgG MM patients have similar behavior on serum M-protein kinetics for the first 60 weeks even with higher exposure and similar progression free survival compared to IgG MM patients supporting the non-dose adjustment based on IgG status. Clinical trial simulation of the ICARIA-MM Isa-Pd regimen demonstrated that switching all patients on treatment at 6 months to a monthly Isa regimen would shorten the median time to progression (TTP) (i.e. increase in serum M-protein greater than 25% and an absolute increase greater than 5 g/L compared to nadir) by 4.1 weeks and would shorten median PFS by 2.3 weeks (from 14.03 to 13.45 months). Based on TTP criteria, patients with no risk of earlier progression (57.7%) due to 6 months switch tend to have lower baseline tumor burden (lower serum M-protein and lower percent of bone marrow plasma cell) and better prognostic factors (higher glomerular filtration rate, higher albumin, lower β2 microglobulin). At 6 months, 85% of these patients had predicted stable "at least" VGPR status. Conclusions: Trial simulations supported the choice of the approved isatuximab 10 mg/kg QW/Q2W regimen and showed that switching to a monthly Isa regimen after 6 months may reduce clinical benefit in overall population. However, a subpopulation of patients with good prognosis and obtaining stable at least VGPR status by 6 months may switch to a monthly regimen after 6 months without compromising disease progression risk; this hypothesis will be tested in a prospective clinical trial. Model-based drug development has been successfully applied to support treatment decisions in RRMM patients. Disclosures Thai: Sanofi: Current Employment. Gaudel-Dedieu:Sanofi: Current Employment. Cerou:Sanofi: Current Employment. Sebastien:Sanofi: Current Employment. van de Velde:Sanofi: Current Employment, Current equity holder in publicly-traded company. Semiond:Sanofi: Current Employment. Veyrat-Follet:Sanofi: Current Employment.

The Anabolic Response to Dietary Protein Is Not Limited by the Maximal Stimulation of Protein Synthesis in Healthy Older Adults: A Randomized Crossover Trial

We have recently demonstrated in young adults that an anabolic response with mixed meal protein intake above ~35 g/meal, previously recognized as an “optimal” protein dose, was further stimulated. However, it is unknown if this applies to older adults. We therefore examined anabolic response to a mixed meal containing either 35 g (MOD, moderate amount of protein) or 70 g (HIGH, high amount of protein) in a randomized cross-over metabolic study in older adults (n = 8). Primed continuous infusions of L-[2H5] phenylalanine and L-[2H2]tyrosine were performed to determine whole-body protein kinetics and muscle protein fractional synthesis rate (MPS) in basal fasted and fed states. Whole-body protein kinetics (NB, net protein balance; PS, protein synthesis; PB, protein breakdown) and MPS was expressed as changes from the baseline post-absorptive state. Consistent with our previous findings in young adults, both feedings resulted in a positive NB, with HIGH being more positive than MOD. Furthermore, NB (expressed as g protein∙240 min) increased linearly with an increasing amount of protein intake, expressed relative to lean body mass. The positive NB was achieved due mainly to the suppression of PB in both MOD and to a greater extent HIGH, while PS was only increased in HIGH. Consistent with the whole-body data, MPS was significantly higher in HIGH than MOD. Plasma concentrations of essential amino acids and insulin were greater in HIGH vs. MOD. We conclude that in the context of mixed meals, whole-body anabolic response linearly increases with increasing protein intake primarily through the suppression of PB, and MPS was further stimulated with protein intake above the previously considered “optimal” protein dose in older adults.

Early alphavirus replication dynamics in single cells reveal a passive basis for superinfection exclusion

SummaryWhile decades of research have elucidated many steps in the alphavirus lifecycle, the earliest replication dynamics have remained unclear. This missing time window has obscured early replicase strand synthesis behavior and prevented elucidation of how the resulting activity gives rise to a superinfection exclusion environment, one of the fastest competitive phenotypes among viruses. Using quantitative live-cell and single-molecule imaging, we characterize the strand preferences of the viral replicase in situ, and measure protein kinetics in single cells over time. In this framework, we evaluate competition between alphaviruses, and uncover that early superinfection exclusion is actually not a binary and unidirectional process, but rather a graded and bidirectional viral interaction. In contrast to competition between other viruses, alphaviruses demonstrate a passive basis for superinfection exclusion, emphasizing the utility of analyzing viral kinetics within single cells.

A Whole-Grain Diet Improves Whole-Body Protein Turnover Compared to a Macronutrient-Matched Refined-Grain Diet in Adults with Overweight/Obesity

Objectives We investigated the effect of consuming a whole-grain diet on whole-body protein metabolism compared to a macronutrient-matched refined-grain diet in adults with overweight/obesity using labelled amino acids (ClinicalTrials.gov Identifier: NCT01411540). Methods We conducted a randomized, controlled crossover trial in 14 adults with overweight/obesity (age: 40 ± 7 yrs, BMI: 33 ± 5 kg/m2) in which isocaloric, macronutrient-matched whole-grain (WG) and refined-grain (RG) diets were fully provided for two 8-week periods (with a 10-week washout period). Diets differed only in the inclusion of whole grains (50 g/1000 kcal). Body composition was measured via DEXA. Whole-body protein kinetics were assessed before and after each diet in the fasted state (13C-Leucine, primed, constant infusion) and over 24 hours (15N-Glycine, bolus). Protein kinetics were normalized to fat-free mass (FFM). Results Both diets resulted in mild weight loss (WG: −2.0 ± 2.5 kg; RG: −2.9 ± 3.3 kg; both P = 0.01 compared to baseline). Fasted-state leucine kinetics revealed greater protein synthesis (WG: 205 ± 61 µmol/kgFFM/hr; RG: 178 ± 36 µmol/kgFFM/hr; P = 0.04) and protein breakdown (WG: 235 ± 68 µmol/kgFFM/hr; RG: 203 ± 40 µmol/kgFFM/hr, P = 0.03) on a WG vs RG diet. This resulted in a more negative fasted-state net balance on a WG diet (WG: −30 ± 8 µmol/kg/hr; RG: −25 ± 6 µmol/kg/hr, P = 0.02). In contrast, 24-hour whole-body protein turnover measured by the end-product method (15N-Glycine), revealed greater protein synthesis (WG: 316 ± 135 mg protein/kgFFM/hr; RG: 250 ± 94 mg protein/kgFFM/hr) with no difference in protein breakdown, yielding a more positive 24-hr net balance on a WG diet (WG: 31 ± 21 mg protein/kgFFM/hr; RG: 10 ± 34 mg protein/kgFFM/hr). Conclusions A whole-grain diet increases whole-body leucine flux and results in a greater 24-hr net protein balance in adults with overweight/obesity compared to a refined-grain diet. This trial suggests whole-grains have an independent effect on protein metabolism and may benefit adults with overweight/obesity. Funding Sources This research was supported by the NIH (UL1 RR024989, T32DK007319 (JPK); T32AT004094 (JTM – trainee)) and an investigator-initiated grant from Nestle (JPK). Nestle Product Technology Center and Cereal Partners Worldwide provided the study meals and foods.