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Duchenne muscular dystrophy (DMD) results in a progressive loss of functional skeletal muscle mass (MM) and replacement with fibrofatty tissue. Accurate evaluation of MM in DMD patients has not previously been available. Our objective was to measure MM using the D3creatine (D3Cr) dilution method and determine its relationship with strength and functional capacity in patients with DMD over a wide range of ages. Subjects were recruited for participation in a 12 month, longitudinal, observational study. Here, we report the baseline data. A 20 mg dose of D3Cr dissolved in water was ingested by 92 patients with DMD (ages 4-25 years) followed later with a fasting urine sample. Enrichment of D3creatinine was determined by liquid chromatography-mass spectrometry analysis. The North Star Ambulatory Assessment (NSAA) total score was determined for ambulatory participants, and the Performance of Upper Limb (PUL 2.0) total score and grip strength for all participants. We observed a significant age-associated increase in body weight along with a substantial decrease in MM/body weight (%MM). MM and %MM were associated with PUL score (r = 0.517, P

Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol, the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared with lean subjects, and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multiomic phenotyping demonstrated that adipocyte-specific [Lpin1.sup.-/-] mice had a metabolically unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of metabolically associated steatohepatitis that was exacerbated by high-fat diets. We conclude that adipocyte lipin 1-mediated lipid storage is vital for preserving adipose tissue and systemic metabolic health, and its loss predisposes mice to metabolically associated steatohepatitis., Introduction Adipose tissue plays essential roles in maintaining metabolic homeostasis by serving as a fat reservoir (lipogenesis) and a secretory organ that releases hormones and other biological factors that signal [...]

BackgroundTraditionally, weight loss (WL) trials utilize dual energy X-ray absorptiometry (DXA) to measure lean mass. This method assumes lean mass, as the sum of all non-bone and non-fat tissue, is a reasonable proxy for muscle mass. In contrast, the D3 -creatine (D3 Cr) dilution method directly measures whole body skeletal muscle mass, although this method has yet to be applied in the context of a geriatric WL trial. The purpose of this project was to (1) describe estimates of change and variability in D3 Cr muscle mass in older adults participating in an intentional WL intervention and (2) relate its change to other measures of body composition as well as muscle function and strength.MethodsThe INVEST in Bone Health trial (NCT04076618), used as a scaffold for this ancillary pilot project, is a three-armed, 12-month randomized, controlled trial designed to determine the effects of resistance training or weighted vest use during intentional WL on a battery of musculoskeletal health outcomes among 150 older adults living with obesity. A convenience sample of 24 participants (n = 8/arm) are included in this analysis. At baseline and 6 months, participants were weighed, ingested a 30 mg D3 Cr tracer dose, provided a fasted urine sample 3-6 days post-dosage, underwent DXA (total body fat and lean masses, appendicular lean mass) and computed tomography (mid-thigh and trunk muscle/intermuscular fat areas) scans, and performed 400-m walk, stair climb, knee extensor strength, and grip strength tests.ResultsParticipants were older (68.0 ± 4.4 years), mostly White (75.0%), predominantly female (66.7%), and living with obesity (body mass index: 33.8 ± 2.7 kg/m2 ). Six month total body WL was -10.3 (95% confidence interval, CI: -12.7, -7.9) kg. All DXA and computed tomography-derived body composition measures were significantly decreased from baseline, yet D3 Cr muscle mass did not change [+0.5 (95% CI: -2.0, 3.0) kg]. Of muscle function and strength measures, only grip strength significantly changed [+2.5 (95% CI: 1.0, 4.0) kg] from baseline.ConclusionsAmong 24 older adults, significant WL with or without weighted vest use or resistance training over a 6-month period was associated with significant declines in all bioimaging metrics, while D3 Cr muscle mass and muscle function and strength were preserved. Treatment assignment for the trial remains blinded; therefore, full interpretation of these findings is limited. Future work in this area will assess change in D3 Cr muscle mass by parent trial treatment group assignment in all study participants.

BackgroundGiven limited experience in applying the creatine-(methyl-D3) (D3Cr) dilution method to measure skeletal muscle mass (SMM) in young children, the feasibility of deployment in a fielding setting and performance of the method was assessed in a cohort of 4-year-old children in Dhaka, Bangladesh.MethodsFollowing D3Cr oral dose (10 mg) administration, single fasting urine samples were collected at 2-4 days (n = 100). Twenty-four-hour post-dose collections and serial spot urine samples on days 2, 3 and 4 were obtained in a subset of participants (n = 10). Urinary creatine, creatinine, D3Cr and D3-creatinine enrichment were analyzed by liquid chromatography-tandem mass spectrometry. Appendicular lean mass (ALM) was measured by dual-energy x-ray absorptiometry and grip strength was measured by a hand-held dynamometer.ResultsSMM was measured successfully in 91% of participants, and there were no adverse events. Mean ± SD SMM was greater than ALM (4.5 ± 0.4 and 3.2 ± 0.6 kg, respectively). Precision of SMM was low (intraclass correlation = 0.20; 95% CI: 0.02, 0.75; n = 10). Grip strength was not associated with SMM in multivariable analysis (0.004 kg per 100 g of SMM; 95% CI: -0.031, 0.038; n = 91).ConclusionsThe D3Cr dilution method was feasible in a community setting. However, high within-child variability in SMM estimates suggests the need for further optimization of this approach.ImpactThe D3-creatine (D3Cr) stable isotope dilution method was considered a feasible method for the estimation of skeletal muscle mass (SMM) in young children in a community setting and was well accepted among participants. SMM was weakly associated with both dual-energy x-ray absorptiometry-derived values of appendicular lean mass and grip strength. High within-child variability in estimated values of SMM suggests that further optimization of the D3Cr stable isotope dilution method is required prior to implementation in community research settings.

BACKGROUND: The D3-creatine (D3Cr) dilution method provides a direct measure of skeletal muscle. The aim of this study was to compare the association of D3Cr muscle mass with lean body mass (LBM) measured by dual-energy x-ray absorptiometry (DXA) and examine its relation with physical function in postmenopausal women. METHODS: Seventy-four community-dwelling women (mean age 82.3 ± 5.4) participated in this pilot study from the Buffalo, New York clinical site of the Womens Health Initiative (WHI). Participants attended a clinic visit which included anthropometric measures, blood draw, DXA scan, measures of physical function, and initiated the D3Cr protocol. Physical function was evaluated using hand grip strength, short physical performance battery (SPPB), and RAND-36 physical function scale. Descriptive statistics and logistic regression models were used to examine the associations of D3Cr muscle mass with functional outcomes. RESULTS: D3-creatine muscle mass was moderately correlated with DXA LBM (r = 0.50) and DXA appendicular lean mass (ALM) (r = 0.50). Individuals with high D3Cr muscle mass (%) had higher physical function compared to individuals with low muscle mass (%), indicated by high scores on SPPB (odds ratio [OR] = 5.24; 95% confidence interval [CI]: 1.40, 19.58). We observed stronger relationships between high D3Cr and physical function than either DXA LBM (OR = 3.40; 95% CI: 0.88, 13.11) or DXA ALM (OR = 4.15; 95% CI: 1.10, 15.68) and physical function. CONCLUSIONS: Our findings provide strong preliminary data for the associations of D3Cr muscle mass with measures of physical function in older women. These findings support and extend prior work on D3Cr muscle mass in older men.

Chronic glucocorticoid exposure causes insulin resistance and muscle atrophy in skeletal muscle. We previously identified phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1) as a primary target gene of skeletal muscle glucocorticoid receptors involved in the glucocorticoid-mediated suppression of insulin action. However, the in vivo functions of Pik3r1 remain unclear. Here, we generated striated muscle-specific Pik3r1 knockout (MKO) mice and treated them with a dexamethasone (DEX), a synthetic glucocorticoid. Treating wildtype (WT) mice with DEX attenuated insulin activated Akt activity in liver, epididymal white adipose tissue, and gastrocnemius (GA) muscle. This DEX effect was diminished in GA muscle of MKO mice, therefore, resulting in improved glucose and insulin tolerance in DEX-treated MKO mice. Stable isotope labeling techniques revealed that in WT mice, DEX treatment decreased protein fractional synthesis rates in GA muscle. Furthermore, histology showed that in WT mice, DEX treatment reduced GA myotube diameters. In MKO mice, myotube diameters were smaller than in WT mice, and there were more fast oxidative fibers. Importantly, DEX failed to further reduce myotube diameters. Pik3r1 knockout also decreased basal protein synthesis rate (likely caused by lower 4E-BP1 phosphorylation at Thr37/Thr46) and curbed the ability of DEX to attenuate protein synthesis rate. Finally, the ability of DEX to inhibit eIF2α phosphorylation and insulin-induced 4E-BP1 phosphorylation was reduced in MKO mice. Taken together, these results demonstrate the role of Pik3r1 in glucocorticoid-mediated effects on glucose and protein metabolism in skeletal muscle.

BACKGROUNDAn increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD group were also evaluated before and after a diet-induced weight loss of 10%.RESULTSThe contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese, and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation.

Duchenne muscular dystrophy (DMD) results in a progressive loss of functional skeletal muscle mass (MM) and replacement with fibrofatty tissue. Accurate evaluation of MM in DMD patients has not previously been available. Our objective was to measure MM using the D3creatine (D3Cr) dilution method and determine its relationship with strength and functional capacity in patients with DMD over a wide range of ages. Subjects were recruited for participation in a 12 month, longitudinal, observational study. Here, we report the baseline data. A 20 mg dose of D3Cr dissolved in water was ingested by 92 patients with DMD (ages 4–25 years) followed later with a fasting urine sample. Enrichment of D3creatinine was determined by liquid chromatography‐mass spectrometry analysis. The North Star Ambulatory Assessment (NSAA) total score was determined for ambulatory participants, and the Performance of Upper Limb (PUL 2.0) total score and grip strength for all participants. We observed a significant age‐associated increase in body weight along with a substantial decrease in MM/body weight (%MM). MM and %MM were associated with PUL score (r = 0.517, P < 0.0001 and r = 0.764, P < 0.0001 respectively). The age‐associated decrease in MM and %MM was strongly associated with ambulatory status. We observed very little overlap in %MM between ambulant and non‐ambulant subjects, suggesting a threshold of 18–22% associated with loss of ambulation. MM is substantially diminished with advancing age and is highly related to clinically meaningful functional status. The D3Cr dilution method may provide a biomarker of disease progression and therapeutic efficacy in patients with DMD or other neuromuscular disorders. Key points: The non‐invasive D3creatine dilution method provides novel data on whole body functional muscle mass (MM) in a wide range of ages in patients with DMD and reveals profoundly low functional MM in older non‐ambulant patients.The difference in %MM between ambulant and non‐ambulant subjects suggests a threshold for loss of ambulatory ability between 18 and 22% MM.The data suggest that as functional MM declines with age, maintaining a lower body weight may help to conserve ambulatory ability. [ABSTRACT FROM AUTHOR]

Background: There is emerging evidence that cancer and its treatments may accelerate the normal aging process, increasing the magnitude and rate of decline in functional capacity. This accelerated aging process is hypothesized to hasten the occurrence of common adverse age-related outcomes in cancer survivors, including loss of muscle mass and decrease in physical function. However, there is no data describing age-related loss of muscle mass and its relation to physical function in the long-term in cancer survivors. Methods: This study protocol describes the use of a novel method of muscle mass measurement, D3-creatine dilution method (D3Cr), in a large sample (n~6000) of community dwelling postmenopausal women from the Women's Health Initiative (WHI). D3Cr will be used to obtain a direct measure of muscle mass remotely. Participants will be drawn from two sub-cohorts embedded within the WHI that have recently completed an in-home visit. Cancer survivors will be drawn from the Life and Longevity After Cancer (LILAC) cohort, and cancer-free controls will be drawn from the WHI Long Life Study 2. The overall objective of this study is to examine the antecedents and consequences of low muscle mass in cancer survivors. The study aims are to: 1) create age-standardized muscle mass percentile curves and z-scores to characterize the distribution of D3- muscle mass in cancer survivors and non-cancer controls, 2) compare muscle mass, physical function, and functional decline in cancer survivors and non- cancer controls, and 3) use machine learning approaches to generate multivariate risk-prediction algorithms to detect low muscle mass. Discussion: The D3Cr method will transform our ability to measure muscle mass in large-scale epidemiologic research. This study is an opportunity to advance our understanding of a key source of morbidity among older and long-term female cancer survivors. This project will fill knowledge gaps, including the antecedents and consequences of low muscle mass, and use innovative methods to overcome common sources of bias in cancer research. The results of this study will be used to develop interventions to mitigate the harmful effects of low muscle mass in older adults and promote healthy survivorship in cancer survivors in the old (>65) and oldest-old (>85) age groups. [ABSTRACT FROM AUTHOR]

Background How magnetic resonance (MR) derived thigh muscle volume and deuterated creatine dilution derived muscle mass (D3Cr muscle mass) differentially relate to strength, fitness, and other functions in older adults—and whether associations vary by sex—is not known. Methods Men (N  = 345) and women (N  = 482) aged ≥70 years from the Study of Muscle, Mobility, and Aging completed leg extension strength (1-repetition max) and cardiopulmonary exercise testing to assess fitness (VO2peak). Correlations and adjusted regression models stratified by sex were used to assess the association between muscle size measures, study outcomes, and sex interactions. Results D3Cr muscle mass and MR thigh muscle volume were correlated (men: r  = 0.62, women: r  = 0.51, p  < .001). Each standard deviation (SD) decrement in D3Cr muscle mass was associated with lower 1-repetition max strength (−14 kg men, −4 kg women, p  < .001 for both; p -interaction = .003) and lower VO2peak (−79 mL/min men, −30 mL/min women, p  < .001 for both, p -interaction:.016). Each SD decrement in MR thigh muscle volume was also associated with lower strength (−32 kg men, −20 kg women, p  < .001 for both; p -interaction = .139) and lower VO2peak (−217 mL/min men, −111 mL/min women, p  < .001 for both, p -interaction = .010). There were associations, though less consistent, between muscle size or mass with physical performance and function; associations varied by sex. Conclusions Less muscle—measured by either D3Cr muscle mass or MR thigh muscle volume—was associated with lower strength and fitness. Varied associations by sex and assessment method suggest consideration be given to which measurement to use in future studies. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated both energy restriction (ER) and higher protein (HP), lower carbohydrate (LC) diets downregulate hepatic de novo lipogenesis. Little is known about the independent and combined impact of ER and HP/LC diets on tissue‐specific lipid kinetics in leptin receptor‐deficient, obese rodents. This study investigated the effects of ER and dietary macronutrient content on body composition; hepatic, subcutaneous adipose tissue (SAT), and visceral AT (VAT) lipid metabolic flux (2H2O‐labeling); and blood and liver measures of cardiometabolic health in six‐week‐old female obese Zucker rats (Leprfa+/fa+). Animals were randomized to a 10‐week feeding intervention: ad libitum (AL)‐HC/LP (76% carbohydrate/15% protein), AL‐HP/LC (35% protein/56% carbohydrate), ER‐HC/LP, or ER‐HP/LC. ER groups consumed 60% of the feed consumed by AL. AL gained more fat mass than ER (P‐energy = 0.012) and HP/LC gained more fat mass than HC/LP (P‐diet = 0.025). Hepatic triglyceride (TG) concentrations (P‐interaction = 0.0091) and absolute hepatic TG synthesis (P‐interaction = 0.012) were lower in ER‐HP/LC versus ER‐HC/LP. ER had increased hepatic, SAT, and VAT de novo cholesterol fractional synthesis, absolute hepatic cholesterol synthesis, and serum cholesterol (P‐energy≤0.0035). A HP/LC diet, independent of energy intake, led to greater gains in fat mass. A HP/LC diet, in the context of ER, led to reductions in absolute hepatic TG synthesis and TG content. However, ER worsened cholesterol metabolism. Increased adipose tissue TG retention with the HP/LC diet may reflect improved lipid storage capacity and be beneficial in this genetic model of obesity. [ABSTRACT FROM AUTHOR]

Background: Despite evidence that low muscle increases the risk of chemotoxicity, most chemotherapies are dosed on body surface area without considering body composition. Among 178 patients with colon cancer, we assessed muscle and adipose tissue with multiple techniques and examined their associations with relative dose intensity (RDI) and adverse events. Methods: We estimated (i) cross-sectional skeletal muscle area (SMA) and total adipose tissue (TAT) area at L3 from computed tomography (CT); (ii) appendicular lean mass (ALM) and total body fat (TBF) mass from dual-energy X-ray absorptiometry (DXA); and (iii) total body skeletal muscle mass using D3-creatine (D3Cr) dilution. We standardized each measurement by its sex-specific standard deviation (SD). The primary outcome was reduced RDI (RDI <85%). The secondary outcome was the number of moderate and severe adverse events during each cycle of chemotherapy. We estimated the associations of muscle and adipose tissue measurements (per SD increase) with reduced RDI using logistic regression and adverse events using generalized estimating equations for repeated measures. Results: Higher CT SMA and DXA ALM were significantly associated with a lower risk of reduced RDI [odds ratios: 0.56 (0.38-0.81) for CT SMA; 0.56 (0.37-0.84) for DXA ALM]. No measurements of muscle or adipose tissue were associated with adverse events. Conclusions: More muscle was associated with improved chemotherapy completion among patients with colon cancer, whereas muscle and adipose tissue were not associated with adverse events. Impact: Considering body composition may help personalize dosing for colon cancer chemotherapy by identifying patients at risk for poor chemotherapy outcomes. [ABSTRACT FROM AUTHOR]

Background In contrast to dual-energy x-ray absorptiometry (DXA), the D3-creatine (D3Cr) dilution method provides a direct measure of skeletal muscle mass and in a cohort of older men has been strongly associated with health-related outcomes. However, sensitivity to detect changes in D3Cr-derived muscle mass due to an intervention is limited. Methods Twenty-one older adults (≥70 years) with low-to-moderate physical function were randomized to a 15-week high-intensity strength training (ST) or a health education (HE) group. Full-body progressive intensity ST was performed 3 days per week. Results The mean age was 82.1 years, with 64% females. After 15 weeks, both D3Cr muscle mass (MM; 2.29 kg; 95% CI: 0.22, 4.36) and DXA appendicular lean mass (ALM; 1.04 kg; 95% CI: 0.31, 1.77) were greater in ST group compared to HE. Baseline correlations between D3Cr MM and DXA ALM (r  = 0.79; 95% CI: 0.53, 0.92) or total lean body mass (LBM; r  = 0.79; 95% CI: 0.52, 0.91) were high. However, longitudinal changes in D3Cr MM were weakly correlated with changes in DXA ALM (r  = 0.19; 95% CI: −0.35, 0.64) and LBM (r  = 0.40; 95% CI: −0.13, 0.76). More participants showed positive response rates, defined as a >5% increase from baseline, with D3Cr MM (80%) than DXA measures (14%–43%). Conclusions A progressive ST intervention in low-functioning older adults increased D3Cr MM and DXA ALM. These data suggest that the D3Cr dilution is potentially sensitive to detect changes in muscle mass in response to resistance exercise training. These results are preliminary and could be used for planning larger trials to replicate these results. [ABSTRACT FROM AUTHOR]

Developing accurate methods to quantify age‐related muscle loss (sarcopenia) could greatly accelerate development of therapies to treat muscle loss in the elderly, as current methods are inaccurate or expensive. The current gold standard method for quantifying sarcopenia is dual‐energy X‐ray absorptiometry (DXA) but does not measure muscle directly—it is a composite measure quantifying "lean mass" (muscle) excluding fat and bone. In humans, DXA overestimates muscle mass, which has led to erroneous conclusions about the importance of skeletal muscle in human health and disease. In animal models, DXA is a popular method for measuring lean mass. However, instrumentation is expensive and is potentially limited by anesthesia concerns. Recently, the D3‐creatine (D3Cr) dilution method for quantifying muscle mass was developed in humans and rats. This method is faster, cheaper, and more accurate than DXA. Here, we demonstrate that the D3Cr method is a specific assay for muscle mass in mice, and we test associations with DXA and body weight. We evaluated the D3Cr method compared to DXA‐determined lean body mass (LBM) in aged mice and reported that DXA consistently overestimates muscle mass with age. Overall, we provide evidence that the D3Cr dilution method directly measures muscle mass in mice. Combined with its ease of use, accessibility, and non‐invasive nature, the method may prove to more quickly advance development of preclinical therapies targeting sarcopenia. [ABSTRACT FROM AUTHOR]