bims-ensmum 2026-10-25 papers

Mol Nutr Food Res. 2026 Oct;70(19): e70628

Whole-Food Protein Sources Differentially Modulate Postprandial Plasma Dileucine Profiles in the Post-Exercise State.

Žan Zupančič, Geoffrey M Provenzano, Calvin Chen, Gena L Irwin, Alexander V Ulanov, Nicholas A Burd.

Dileucine, a leucine-containing dipeptide, may enhance anabolic signaling more than leucine alone. This study examined postprandial plasma dileucine and leucine concentrations after ingesting animal- and plant- whole foods and their association with muscle protein synthesis rates (MPS). Secondary analysis was performed on plasma samples collected from two randomized controlled trials totaling 26 healthy adults (25 ± 4.3 y). Participants consumed low-fat pork (LFP), high-fat ground pork (HFP), complementary rice and beans (COMP), an iso-nitrogenous mixed nutrient beverage (ISO), or a carbohydrate control (CHO). Plasma concentrations and MPS was measured. Plasma dileucine increased significantly only after LFP ingestion (p < 0.05), with a greater 300-min iAUC compared to CHO (p = 0.038). Plasma leucine increased in all conditions except COMP and CHO with LFP demonstrating the highest concentrations (p < 0.05). A modest correlation was observed between dileucine Cmax and the change in MPS (ΔMPS; r = 0.436, p = 0.037), whereas leucine Cmax showed no significant association (r = 0.265, p = 0.102). Whole-food protein sources generally do not elevate plasma dileucine, except for LFP. While dileucine Cmax correlated with ΔMPS, the strength of this relationship suggests dileucine is likely one of several postprandial factors influencing MPS beyond free leucine.

Keywords: animal protein; dileucine; leucine; plant protein; skeletal muscle; whole foods

DOI: https://doi.org/10.1002/mnfr.70628

Exp Gerontol. 2026 Oct 23. pii: S0531-5565(26)00345-1. [Epub ahead of print] 113365

Human serum collected after fermented whey protein supplementation stimulates myocellular growth and protein synthesis: A randomized, double-blind, active-controlled crossover trial.

Kazuki Uemichi, Mito Watanabe, Naomi Yoshii, Kento Nozawa, Risako Mori, Shota Inoue, Yasushi Shinohara, Satoshi Fujita.

BACKGROUND: Age-related anabolic resistance has been proposed as one contributor to skeletal muscle loss in older adults, although its magnitude varies substantially among individuals and experimental conditions. Whey protein stimulates muscle protein synthesis (MPS) through increased circulating amino acid availability and activation of mechanistic target of rapamycin complex 1 (mTORC1), whereas fermented whey protein may exert greater anabolic effects due to enhanced bioactivity. However, its effects on skeletal muscle anabolic and metabolic responses during aging remain unclear.
METHODS: This randomized, double-blind, placebo-controlled, crossover study investigated the effects of fermented whey protein ingestion on serum-mediated anabolic and metabolic responses in cultured skeletal muscle cells from young and older males. Participants consumed fermented whey protein (Fermentis) and conventional non-fermented protein (control whey) on separate occasions. Differentiated C2C12 myotubes were cultured in medium containing 10% postprandial human serum to evaluate MPS, mitochondrial-related signaling, and myotube hypertrophy.
RESULTS: Serum obtained after Fermentis ingestion increased myotube diameter compared with serum obtained after conventional whey protein, with no age × protein interaction. For MPS, we observed a significant age × protein interaction, and MPS was greater in myotubes treated with post-Fermentis serum from older donors than from young donors. In addition, serum obtained after Fermentis ingestion markedly enhanced S6K1 Thr389 phosphorylation and oxidative metabolism-related signaling molecules compared with non-fermented protein treatment.
CONCLUSIONS: The present findings may provide mechanistic insights into the development of nutritional strategies to attenuate age-associated anabolic resistance and improve skeletal muscle oxidative metabolic function.

Keywords: Amino acids; Anabolic resistance; Muscle protein synthesis; Serum; Skeletal muscle cells; Whey protein

DOI: https://doi.org/10.1016/j.exger.2026.113365

J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70407

Integrated Single-Myofibre Multi-Omics Correlates Inflammatory State to Myosin Energetics in ICU-Acquired Weakness.

Alexandra M Winant, Roger Moreno-Justicia, Lucia Paolini, Wout J Claassen, Coen A C Ottenheijm, Atul S Deshmukh, Stefano Cattaneo, Simone Piva, Nicola Latronico, Robert A E Seaborne, Julien Ochala.

BACKGROUND: Skeletal muscle atrophy is a pervasive complication of critical illness that worsens survival and recovery, yet remains poorly explained by current clinical or molecular markers.
METHODS: To directly connect disease-associated molecular states to the contractile machinery, this study combined sequential functional, transcriptomic and proteomic profiling of the same single human skeletal myofibres from critically ill patients in the intensive care unit with acquired weakness (ICU-AW) and controls. This integrated approach provides a framework for validating molecular signals directly within the cellular and biomechanical context.
RESULTS: Differential expression analyses between control and ICU-AW myofibres show marked donor-level heterogeneity, with no differentially expressed features (FDR < 0.05). Ranked gene set enrichment analyses revealed distinct transcriptional and proteomic signatures between conditions, as well as a subtle yet conserved myofibre state enriched in ICU-AW, characterised by inflammatory and chemotactic gene programmes, intracellular structural remodelling and bioenergetic adaptation. Nineteen features were significantly (FDR < 0.05) altered at both RNA and protein levels from the same myofibre. Overall, these 19 overlapping features link an inflammatory transcriptional landscape to a proteomic shift toward mitochondrial and translational machinery, revealing a coordinated stress-adaptation programme with selective post-translational control in fibres from patients with ICU-AW. Further integration with the functional dataset revealed fibres in this state displayed selectively disrupted myosin dynamics, evidenced by prolonged ATP turnover time of myosin heads in their super-relaxed conformation, suggesting altered myosin energetics as a contributor to muscle dysfunction.
CONCLUSIONS: These findings define a discrete, disease-associated myofibre state and validate a proof-of-concept integrative single-fibre framework for connecting multi-omic heterogeneity to molecular motor function in complex human disease. The identification of coordinated transcriptomic and proteomic programmes, validated through functional measurement, suggests that targeting this fibre state may offer new therapeutic opportunities in ICU-acquired dysfunction and related muscle disorders.

Keywords: critical illness; multi‐omics; muscle weakness; myosin energetics; single‐fibre analysis; skeletal muscle heterogeneity

DOI: https://doi.org/10.1002/jcsm.70407

Scand J Med Sci Sports. 2026 Nov;pii: e70383. [Epub ahead of print]36(11):

Endurance Training Improves Insulin Sensitivity, Metabolic Flexibility, and Mitochondrial Function in Type 2 Diabetes.

Maria Hansen, Sophie Møller, Ida Blom, Kristine K Lange, Andreas K Ziegler, Johanne E Farlov, Jacob Borch, Sofie A Hesselager, Jonathan K Hansen, Anna Liebmann, Mette H Dal, Thorbjörn Åkerström, Jørn W Helge, Ylva Hellsten, Flemming Dela.

To determine how endurance training influences insulin sensitivity, metabolic flexibility, and mitochondrial function in individuals with and without type 2 diabetes (T2D). Insulin sensitivity (2-step hyperinsulinaemic-isoglycaemic clamp), metabolic flexibility, and mitochondrial respiratory capacity and H2O2 emission were assessed in participants with T2D (n = 15) and controls (n = 14) before and after 12 weeks of supervised endurance training. Sensitivity analyses were performed using linear mixed-effects models including all available participants. At baseline, glucose clearance was lower in individuals with T2D compared with controls. Training increased glucose clearance (mL/min/kg FFM) in both groups, with larger model-derived improvements in T2D (Step 1: +1.43 [0.88-1.97]; Step 2: +3.18 [2.12-4.23]) than in controls (Step 1: +0.76 [0.21-1.31]; Step 2: +1.49 [0.53-2.45]). The group × time interaction was significant at the higher insulin step. Metabolic flexibility to fat-but not glucose-was reduced in T2D and improved modestly with training. Mitochondrial respiratory capacity did not differ between groups; however, training decreased mitochondria-specific respiration and H2O2 emission normalized to CS activity and respiration. Endurance training enhances insulin sensitivity and fat oxidation in individuals with T2D and induces favorable mitochondrial adaptations, despite the absence of intrinsic mitochondrial dysfunction.

Keywords: hyperinsulinaemic clamp; metabolic flexibility; mitochondrial respiratory capacity; non‐randomized study; peak fat oxidation; reactive oxygen species

DOI: https://doi.org/10.1111/sms.70383

Nat Commun. 2026 10 19. pii: 10702. [Epub ahead of print]17(1):

Miro1 mediates skeletal muscle insulin resistance in type 2 diabetes.

Elizabeth C Heintz, Wagner S Dantas, Analisa L Taylor, Elizabeth R M Zunica, Kathryn P Belmont, Jackson M Slone, Jacob T Mey, Robbie Beyl, Bolormaa Vandanmagsar, Hailey A Parry, Peter Ajayi, Brian Glancy, Christopher L Axelrod, John P Kirwan.

Imbalanced skeletal muscle mitochondrial dynamics contribute to the onset and progression of type 2 diabetes (T2D) by mechanisms that remain incompletely understood. Here, we examined the role of Mitochondrial Rho GTPase 1 (Miro1), an outer mitochondrial membrane enzyme, in regulating skeletal muscle insulin action and glucose homeostasis in type 2 diabetes (T2D). In a cross-sectional clinical study, we show that Miro1 accumulates in the skeletal muscle of patients with obesity and T2D, which was further replicated in mouse models of T2D. This accumulation is explained by inadequate insulin-mediated interaction between AKT and Miro1 at the outer mitochondrial membrane. In a randomized controlled trial (NCT02977442), we show that exercise training relieves skeletal muscle Miro1 accumulation while improving insulin sensitivity in patients with T2D. Muscle-specific Miro1 deletion improves oxidative capacity and insulin sensitivity in mice and cells. Taken together, these data support a key regulatory role for skeletal muscle Miro1 in the pathophysiology of T2D. ClinicalTrials.gov Identifier: NCT02977442.

DOI: https://doi.org/10.1038/s41467-026-77278-6