Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG.

OBJECTIVES: Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss. METHODS: We quantified genomic, metabolomic, and proteomic changes in cultured skeletal muscle cells and mouse models of IDH-mutant leukemia using RNA sequencing, mass spectrometry, and computational modeling. RESULTS: D2-HG impairs NADH redox homeostasis in myotubes. Increased NAD+ levels drive activation of nuclear deacetylase Sirt1, which causes deacetylation and activation of LC3, a key regulator of autophagy. Using LC3 mutants, we confirm that deacetylation of LC3 by Sirt1 shifts its distribution from the nucleus into the cytosol, where it can undergo lipidation at pre-autophagic membranes. Sirt1 silencing or p300 overexpression attenuated autophagy activation in myotubes. In vivo, we identified increased muscle atrophy and reduced grip strength in response to D2-HG in male vs. female mice. In male mice, glycolytic intermediates accumulated, and protein expression of oxidative phosphorylation machinery was reduced. In contrast, female animals upregulated the same proteins, attenuating the phenotype in vivo. Network modeling and machine learning algorithms allowed us to identify candidate proteins essential for regulating oncometabolic adaptation in mouse skeletal muscle. CONCLUSIONS: Our multi-omics approach exposes new metabolic vulnerabilities in response to D2-HG in skeletal muscle and provides a conceptual framework for identifying therapeutic targets in cachexia.

Quality of Life Assessment in Older Adults with Dementia: A Systematic Review.

INTRODUCTION: In the absence of a cure, dementia is often managed by minimizing risk factors contributing to quality of life (QOL). Attitudes to dementia in older adults may differ from those in relatively younger adults. The aim was to conduct a systematic review of the literature to determine how QOL was assessed in adults, 65 years and older with dementia, and identify factors that influence the reported scores. METHODS: A systematic review of full-text articles addressing QOL in older adults with dementia, published in English from January 1995 to September 2020, was conducted using PubMed and PsycINFO. We included studies that assessed QOL and involved participants 65 years and older. Studies were evaluated for inclusion by 2 independent pairs of reviewers. We assessed the quality of the studies using the Joanna Briggs Institute's Critical Appraisal Checklist. Study characteristics and findings were summarized. Analysis was by narrative synthesis. We identified social and clinical factors influencing QOL scores. RESULTS: Of the 1,010 articles identified, 19 met the inclusion criteria. These 19 studies involved 6,279 persons with dementia, with sample sizes from 32 to 1,366. Mean age of participants ranged from 77.1 to 86.6 years. Five measurement tools were identified; Quality of Life in Alzheimer Disease (QOL-AD), Alzheimer Disease-Related Quality of Life (ADRQL), Quality of Life in Late-Stage Dementia (QUALID), QUALIDEM (a dementia-specific QOL tool), and DEMQOL (health-related QOL for people with dementia). Self-ratings of QOL were higher than proxy ratings. Factors commonly influencing self-ratings of QOL included depression, functional impairment, and polypharmacy. Common factors that influenced proxy ratings included functional impairment, presence of neuropsychiatric symptoms, cognitive impairment, and caregiver burden. CONCLUSION: In evaluating QOL in dementia, self- and proxy reports may complement each other to ensure that all perspectives are addressed.

Regional variations in medical trainee diet and nutrition counseling competencies: Machine learning-augmented propensity score analysis of a prospective multi-site cohort study.

BACKGROUND: Medical professionals and students are inadequately trained to respond to rising global obesity and nutrition-related chronic disease epidemics, primarily focusing on cardiovascular disease. Yet, there are no multi-site studies testing evidence-based nutrition education for medical students in preventive cardiology, let alone establishing student dietary and competency patterns. METHODS: Cooking for Health Optimization with Patients (CHOP; NIH NCT03443635) was the first multi-national cohort study using hands-on cooking and nutrition education as preventive cardiology, monitoring and improving student diets and competencies in patient nutrition education. Propensity-score adjusted multivariable regression was augmented by 43 supervised machine learning algorithms to assess students outcomes from UT Health versus the remaining study sites. RESULTS: 3,248 medical trainees from 20 medical centers and colleges met study criteria from 1 August 2012 to 31 December 2017 with 60 (1.49%) being from UTHealth. Compared to the other study sites, trainees from UTHealth were more likely to consume vegetables daily (OR 1.82, 95%CI 1.04-3.17, p=0.035), strongly agree that nutrition assessment should be routine clinical practice (OR 2.43, 95%CI 1.45-4.05, p=0.001), and that providers can improve patients' health with nutrition education (OR 1.73, 95%CI 1.03-2.91, p=0.038). UTHealth trainees were more likely to have mastered 12 of the 25 competency topics, with the top three being moderate alcohol intake (OR 1.74, 95%CI 0.97-3.11, p=0.062), dietary fats (OR 1.26, 95%CI 0.57-2.80, p=0.568), and calories (OR 1.26, 95%CI 0.70-2.28, p=0.446). CONCLUSION: This machine learning-augmented causal inference analysis provides the first results that compare medical students nationally in their diets and competencies in nutrition education, highlighting the results from UTHealth. Additional studies are required to determine which factors in the hands-on cooking and nutrition curriculum for UTHealth and other sites produce optimal student - and, eventually, preventive cardiology - outcomes when they educate patients in those classes.