Esther E. Dupont-Versteegden

Objectives: To examine physical activity levels in survivors of critical illness across 6 months, and to understand the barriers and facilitators of physical activity. Design: Prospective, longitudinal, convergent mixed-methods study. Setting: Functional testing laboratory. Patients: Adults admitted to the ICU for at least 72 hours with acute respiratory failure or sepsis. Interventions: None. Measurements and Main Results: Patients wore an accelerometer starting at hospital discharge, at 3- and 6-month follow-up to quantify daily step counts. At 6 months, physical function and patient-reported outcomes were collected in-person, with a subset of participants completing semi-structured interviews. Eighty-two patients were enrolled, with 67 (82%) having physical activity data with median age of 60 years (interquartile range [IQR], 52–66 yr), 54% male, and ICU stay 9.0 days [IQR, 5.8–17.0 d]. The median daily steps were 1358 (IQR, 742–2799) in 50 patients at baseline, 2305 (IQR, 1081–3898) in 54 patients at 3 months, and 2826 (IQR, 1609–4781) in 44 patients at 6 months. Higher comorbidity burden and earlier measurement associated with lower step counts. At 6 months, patients walked a mean of 344 ± 169 meters on the 6-minute walk test and reported being sedentary a median of 300 min/days (150–480 min/d). Eleven participants completed interviews, yielding three themes: 1) “a marathon, not a sprint”: the extended ICU recovery trajectory; 2) engagement in physical activity is highly regulated by personal context; 3) value-driven and motivation-informed physical activity decisions. Mixed-methods integration demonstrated that qualitative themes expanded upon quantitative findings to explain nonlinear recovery patterns, contextualizing persistent sedentary behavior, and revealing that motivational and behavioral gaps are not captured by accelerometry. Conclusions: Survivors showed gradual improvement in daily steps over 6 months yet remained below recommended activity levels. Survivorship and attrition biases may lead to overestimation of step counts, further warranting larger studies. Integrating quantitative and qualitative data reveals modifiable contextual factors that may inform the design of pragmatic physical activity interventions.

OBJECTIVES: To identify biological findings underlying skeletal muscle dysfunction in adults with critical illness and meta-analyze myofiber cross-sectional area and protein turnover variables. DATA SOURCES: Six databases were electronically searched from inception to January 2025. STUDY SELECTION: We included original studies reporting biological findings obtained from skeletal muscle biopsies of adults with critical illness. DATA EXTRACTION: Bibliometrics, characteristics of the patients/controls, and biological findings were extracted in duplicate. Descriptive statistics of biological findings were performed. Random-effects meta-analyses investigated mean differences (MDs) in myofiber cross-sectional area and protein turnover compared with controls. DATA SYNTHESIS: From 22,035 titles screened, 75 studies ( n = 2,023 patients; n = 642 controls) published between 1988 and 2024 were included, with 48 unique patient datasets. Biopsies were mainly collected from vastus lateralis (64 [85%] studies) during the first ICU week (50% of studies) and post-ICU (9%). Biological findings included predominant type II myofiber atrophy with necrosis and structural degeneration, mitochondrial dysfunction, inflammatory/fibrotic changes, and upregulated ubiquitin-proteasome/autophagy pathways. Data from six studies ( n = 100 patients; 193 controls) indicated that cross-sectional area was 22% lower in patients with critical illness before (MD, –689 µm ² ; 95% CI, –1265 to –113 µm ² ; p = 0.02) and after (MD, –775 µm ² ; 95% CI, –1512 to –37 µm ² ; p = 0.04) ICU discharge. Across seven studies ( n = 126 patients; 61 controls) protein synthesis was not significantly different in patients with critical illness compared with controls (MD, 0.007%/hr; 95% CI, –0.010 to 0.027; p = 0.36). Protein degradation pathway markers were significantly higher (standardized MD ranging, 0.5–1.7) in data from 11 studies ( n = 439 patients; 163 controls). CONCLUSIONS: Muscle wasting during critical illness reflects multifaceted biological disturbances. While myofiber size is significantly lower in patients with critical illness, pooled analyses show no significant differences in muscle protein synthesis compared with non-ICU controls, whereas protein degradation markers are consistently higher.

Disuse is often suggested as a major driver of quadriceps pathology following anterior cruciate ligament reconstruction (ACLR). This study identifies shared and unique gene signatures that occur early with ACLR and unilateral lower limb suspension (ULLS), highlighting ACLR-specific responses that likely contribute to prolonged quadriceps atrophy and weakness.

Revealing biological mechanisms leading to respiratory muscle dysfunction is essential to improve clinical outcomes in patients with critical illness. The purpose was to identify biological mechanisms associated with respiratory muscle dysfunction in patients with critical illness during mechanical ventilation or sepsis. Six databases were electronically searched from inception to January 2025, examining studies with muscle biopsies. Screening, data collection, and risk-of-bias were conducted in duplicate by two independent assessors. Meta-analysis was performed to determine differences in muscle biological parameters of patients with critical illness requiring mechanical ventilation compared with controls. From 22,036 titles screened, eight studies ( n = 187 patients and n = 161 controls) published between 2000 and 2024 met eligibility criteria. Muscle biopsies were taken between days 1 and 7 in the intensive care unit from the diaphragm ( n = 110; 3 studies), rectus abdominis ( n = 68; 5 studies), external intercostal ( n = 10; 1 study), and latissimus dorsi ( n = 3; 1 study). Diaphragmatic fiber cross-sectional area was 30% smaller (mean difference [95% confidence interval] = −629 [−876, −382] μm ² ), with lower proportion of type II fibers (−1.94 [−3.40, −0.49]%) compared with controls. Diaphragmatic fiber force of patients was more than two standard deviations lower (standardized mean difference = −2.49 [−3.84, −1.14]), and ubiquitinated protein levels were higher (2.09 [−0.14, 4.32]) than controls. Extramyocellular, mitochondrial, and gene expression parameters were assessed in some studies, but low sample size and high heterogeneity prevented meta-analyses. In conclusion, muscle biopsies from ventilated patients revealed atrophy, contractile weakness, and proteolysis markers. Standardized methodologies assessing respiratory muscles are needed to clarify biological mechanisms leading to muscle dysfunction and to guide respiratory muscle interventions.

Introduction Patients who survive admission to intensive care unit (ICU) for critical illness are at high risk of developing muscle atrophy and weakness, commonly diagnosed as ICU-acquired weakness (ICUAW). The development of ICUAW is closely linked to long-term symptoms and impairments known as post-intensive care syndrome (PICS). Despite heightened recognition of impairments, there is limited research supporting effective interventions to improve muscle and physical outcomes after hospital discharge. Prior to developing and testing interventions for ICU survivors, it is imperative to understand the trajectory of muscle and physical function recovery following an ICU stay. The purpose of this study is to longitudinally investigate skeletal muscle health and physical function outcomes after ICU admission. Methods and analysis This protocol describes a single site, prospective, observational study in adult patients who have survived a critical illness (ie, sepsis or acute respiratory failure). Patients will participate in a battery of testing including primary outcomes: muscle power and physical function; and secondary outcomes: muscle strength, muscle size, endurance and physical activity (by accelerometry) at hospital discharge and 3, 6, and 12 months post-discharge. A subset of patients will participate in muscle biopsy and venipuncture. To examine if the trajectory of recovery predicts primary outcomes, we will perform multivariate linear regression models in 150 evaluable patients. To examine differences in molecular and cellular outcomes in plasma and muscle tissue, a control group of community-dwelling adults without history of an ICU stay will be enrolled as a comparator group. Enrolment started on 18 October 2022 with an estimated completion date of 1 August 2027. Ethics and dissemination This protocol was approved by the University of Kentucky Office of Research Integrity Medical Internal Review Board (# 77407), with patients providing informed written consent. We anticipate our findings to establish recovery trajectories, improving the classification of patients who experience sustained physical disability. Improved identification of recovery trajectories of muscle and physical function enables future studies to employ an individually targeted rehabilitation approach, that is, precision medicine, with the goal of improving patient outcomes. The cellular findings will support the development of novel interventions specifically designed for detecting underlying mechanisms. We intend to disseminate findings to patients, healthcare professionals, the public and other relevant groups via conference presentations and manuscripts without publication restrictions. Trial registration number NCT05537298.

Satellite cells comprise a small proportion of mononuclear cells in adult skeletal muscle. Despite their relative rarity, satellite cells have critical functions in muscle adaptation, particularly during prolonged exercise training. The mechanisms by which satellite cells mediate skeletal muscle responsiveness to physical activity throughout the lifespan are still being defined, but epigenetic regulation may play a role. To explore this possibility, we analyzed global DNA methylation patterns in muscle tissue from female mice that engaged in lifelong voluntary unweighted wheel running with or without satellite cells. Satellite cells were ablated in adulthood using the tamoxifen‐inducible Pax7‐DTA model. Compared to sedentary mice, wheel running for 13 months caused muscle DNA methylation differences in the promoter regions of numerous muscle fiber‐enriched genes— Cacgn1 , Dnm2 , Mlip , Myl1 , Myom2 , Mstn , Sgca , Sgcg , Tnnc1 , Tnni2 , Tpm1 , and Ttn —only when satellite cells were present. These genes relate to muscle fiber identity, cytoarchitecture, and size as well as overall muscle function. Epigenetic alterations to such genes are consistent with previously observed histological and in vivo impairments to running adaptation after satellite cell depletion in these same mice. Musk promoter region methylation was affected only in the absence of satellite cells with lifelong running relative to sedentary; this dovetails with work showing that satellite cells influence skeletal muscle innervation. Defining the epigenetic effects of satellite cells on identity genes in muscle fibers after lifelong physical activity provides new directions for how these rare stem cells can promote muscle adaptation and function throughout the lifespan.