CALORIE RESTRICTION AND THE AGING MUSCLE: A MULTISPECIES APPROACH

Aging is associated with a progressive decline in muscle mass, strength, and physical function termed sarcopenia. Sarcopenia is an important risk factor for loss of independence, reduced quality of life, and increased mortality. Calorie restriction (CR) is an effective dietary treatment for several age-related conditions, including sarcopenia. Recent work conducted in our laboratory suggests insulin-like growth factor-1 (IGF-1) is involved in the anti-aging effects of CR. The aim of this work is to understand the role of circulating IGF-1 in CR-induced effects on aging skeletal muscle. Using a multispecies approach, we sought to determine if IGF-1-mediated effects of CR are conserved among mice, nonhuman primates, and humans. As an extension into our investigation of CR and IGF-1 on aging muscle, we conducted an in vivo experiment to examine the role of a CR mimetic, rapamycin, on age-related loss of muscle strength and function. Our results suggest that the effects of CR on aging skeletal muscle are realized through biological changes consistent with regenerative and repair-related mechanisms and a shift in transcriptional profiles towards improved metabolic and inflammatory signaling pathways that promote enhanced mitochondrial function and biogenesis. Collectively, this work demonstrates CR-induced effects on aging muscle are, in part, supported by reduced circulating IGF-1. Further, the CR-mimetic, rapamycin may hold promise as a pharmacological alternative to CR to attenuate loss of muscle strength and function associated with age.Doctor of Philosoph

Dietary carbohydrate intake and high sensitivity C reactive protein in at-risk women and men

Background— The quality and quantity of dietary carbohydrate intake, measured as dietary glycemic load (GL), is associated with a number of cardiovascular disease (CVD) risk factors and, in healthy young women, is related to increased high sensitivity C-reactive protein (hsCRP) concentrations. Our objective was to determine if GL is related to hsCRP and other measures of CVD risk in a population of sedentary, overweight, dyslipidemic middle-aged women and men enrolled in an exercise intervention trial (STRRIDE). Methods— This was a cross-sectional evaluation of the relationships between measures of dietary carbohydrate intake, calculated from food frequency questionnaire data, and CVD risk factors, including plasma hsCRP, measured in 171 subjects. Results— After adjusting for energy intake, GL and other measures of carbohydrate intake were not independently related to hsCRP (P>0.05 for all). In analyses performed separately for each gender, only the quantity of carbohydrate intake was independently related to hsCRP (R2=0.28; P<0.04), and this relationship was present for women but not for men. The strongest relationship identified between GL and any CVD risk factor was for cardiorespiratory fitness (R2=0.12; P<0.02); an elevated GL was associated with a lower level of fitness in all subjects, and this relationship persisted even when the findings were adjusted for energy intake and gender (R2=0.48; P<0.03). Conclusions— In middle-aged, sedentary, overweight to mildly obese, dyslipidemic individuals, consuming a diet with a low GL is associated with better cardiorespiratory fitness. Our findings suggest that the current literature relating carbohydrate intake and hsCRP should be viewed with skepticism, especially in the extension to at-risk populations that include men. Originally published American Heart Journal, Vol. 154, No. 5, Nov 200

Differential microRNA profiles of intramuscular and secreted extracellular vesicles in human tissue-engineered muscle

Exercise affects the expression of microRNAs (miR/s) and muscle-derived extracellular vesicles (EVs). To evaluate sarcoplasmic and secreted miR expression in human skeletal muscle in response to exercise-mimetic contractile activity, we utilized a three-dimensional tissue-engineered model of human skeletal muscle (“myobundles”). Myobundles were subjected to three culture conditions: no electrical stimulation (CTL), chronic low frequency stimulation (CLFS), or intermittent high frequency stimulation (IHFS) for 7 days. RNA was isolated from myobundles and from extracellular vesicles (EVs) secreted by myobundles into culture media; miR abundance was analyzed by miRNA-sequencing. We used edgeR and a within-sample design to evaluate differential miR expression and Pearson correlation to evaluate correlations between myobundle and EV populations within treatments with statistical significance set at p < 0.05. Numerous miRs were differentially expressed between myobundles and EVs; 116 miRs were differentially expressed within CTL, 3 within CLFS, and 2 within IHFS. Additionally, 25 miRs were significantly correlated (18 in CTL, 5 in CLFS, 2 in IHFS) between myobundles and EVs. Electrical stimulation resulted in differential expression of 8 miRs in myobundles and only 1 miR in EVs. Several KEGG pathways, known to play a role in regulation of skeletal muscle, were enriched, with differentially overrepresented miRs between myobundle and EV populations identified using miEAA. Together, these results demonstrate that in vitro exercise-mimetic contractile activity of human engineered muscle affects both their expression of miRs and number of secreted EVs. These results also identify novel miRs of interest for future studies of the role of exercise in organ-organ interactions in vivo

Calorie restriction improves lipid-related emerging cardiometabolic risk factors in healthy adults without obesity: Distinct influences of BMI and sex from CALERIE™ a multicentre, phase 2, randomised controlled trial

Background: For many cardiovascular risk factors there is no lower limit to which further reduction will result in decreased disease risk; this includes values within ranges considered normal for healthy adults. This seems to be true for new emerging metabolic risk factors identified by innovative technological advances. Further, there seems to be ever evolving evidence of differential responses to lifestyle interventions by sex and body compositions in the normal range. In this secondary analysis, we had the opportunity to test these principles for newly identified molecular biomarkers of cardiometabolic risk in a young (21–50 years), normal weight healthy population undergoing calorie restriction for two years. Methods: The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) was a 24-month, multicenter, randomized controlled trial (May 2007-November 2012) in healthy, adults without obesity to evaluate the potential for calorie restriction (CR) to promote anti-aging adaptations, including those associated with disease risk. 218 participants (age 37.9 ± 7.2 years and body mass index (BMI) 25.1 ± 1.7 kg/m2, mean±SD) were randomized 2:1 to 24 months of CR (prescribed as 25% reduction from baseline calorie intake) versus ad libitum (AL). Fasting plasma from baseline, 12, and 24 months was used for assessments of lipoproteins, metabolites, and inflammatory markers using nuclear magnetic resonance spectroscopy. Findings: Averaging 11.9% CR, the CR group had reductions at 12 and 24 months in the cardiovascular disease risk markers, apolipoprotein B and GlycA, and risks for insulin resistance and type 2 diabetes—Lipoprotein Insulin Resistance Index and Diabetes Risk Index (all PCRvsAL≤0.0009). Insulin resistance and diabetes risk improvements resulted from CR-induced alterations in lipoproteins, specifically reductions in triglyceride-rich lipoprotein particles and low-density lipoprotein particles, a shift to larger high-density lipoprotein particles (more effective cholesterol transporters), and reductions in branched chain amino acids (BCAAs) (all PCRvsAL≤0.004). These CR responses were more pronounced in overweight than normal weight participants and greater in men than women. Interpretation: In normal to slightly overweight adults without overt risk factors or disease, 12 months of ∼12% CR improved newly identified risk markers for atherosclerotic cardiovascular disease, insulin resistance and type 2 diabetes. These markers suggest that CR improves risks by reducing inflammation and BCAAs and shifting lipoproteins from atherogenic to cholesterol transporting. Additionally, these improvements are greater for men and for those with greater BMIs indicating sex and BMI-influences merit attention in future investigations of lifestyle-mediated improvements in disease risk factors

Dietary carbohydrate intake and high sensitivity C reactive protein in at-risk women and men

Background— The quality and quantity of dietary carbohydrate intake measured as dietary glycemic load (GL) is associated with a number of cardiovascular disease (CVD) risk factors and in healthy young women is related to increased high sensitivity C-reactive protein (hsCRP) concentrations. Our objective was to determine if GL is related to hsCRP and other measures of CVD risk in a population of sedentary overweight dyslipidemic middle-aged women and men enrolled in an exercise intervention trial (STRRIDE). ethods— This was a cross-sectional evaluation of the relationships between measures of dietary carbohydrate intake calculated from food frequency questionnaire data and CVD risk factors including plasma hsCRP measured in 171 subjects. esults— After adjusting for energy intake GL and other measures of carbohydrate intake were not independently related to hsCRP (P&gt;0.05 for all). In analyses performed separately for each gender only the quantity of carbohydrate intake was independently related to hsCRP (R2=0.28; P&lt;0.04) and this relationship was present for women but not for men. The strongest relationship identified between GL and any CVD risk factor was for cardiorespiratory fitness (R2=0.12; P&lt;0.02); an elevated GL was associated with a lower level of fitness in all subjects and this relationship persisted even when the findings were adjusted for energy intake and gender (R2=0.48; P&lt;0.03). onclusions— In middle-aged sedentary overweight to mildly obese dyslipidemic individuals consuming a diet with a low GL is associated with better cardiorespiratory fitness. Our findings suggest that the current literature relating carbohydrate intake and hsCRP should be viewed with skepticism especially in the extension to at-risk populations that include men. Originally published American Heart Journal Vol. 154 No. 5 Nov 200

Influence of Protein Intake, Race, and Age on Responses to a Weight-Reduction Intervention in Obese Women

BACKGROUND: Women have higher rates of obesity than men and develop more pronounced functional deficits as a result. Yet, little is known about how obesity reduction affects their functional status, including whether their responses differ when protein intake is enhanced. OBJECTIVE: The aim of this study was to confirm the feasibility of delivery of a higher-protein (balanced at each meal) calorie-restricted diet in obese women and determine its efficacy for influencing function and retention of lean mass. METHOD: Obese community-dwelling women [n = 80; body mass index (in kg/m2), in means ± SDs: 37.8 ± 5.9; aged 45–78 y; 58.8% white] were enrolled in a weight-loss (−500 kcal/d) study and randomly assigned to either a Control–Weight-Loss (C-WL; 0.8 g protein/kg body weight) group or a High-Protein–Weight-Loss (HP-WL; 1.2 g protein/kg body weight; 30 g protein 3 times/d) group in a 1:2 allocation. Primary outcomes were function by 6-min walk test (6MWT) and lean mass by using the BodPod (Life Measurement, Inc.) at 0, 4, and 6 mo. RESULTS: Both groups reduced calorie intakes and body weights (P &lt; 0.001), and the feasibility of the HP-WL intervention was confirmed. The 6MWT results improved (P &lt; 0.01) at 4 mo in the HP-WL group and at 6 mo in both groups (P &lt; 0.001). Both groups improved function by several other measures while slightly decreasing (P &lt; 0.01) lean mass (−1.0 kg, C-WL; −0.6 kg, HP-WL). Weight loss was greater in white than in black women at both 4 mo (6.0 ± 3.6 compared with 3.7 ± 3.4 kg; P &lt; 0.02) and 6 mo (7.2 ± 4.8 compared with 4.0 ± 4.7 kg; P &lt; 0.04) and tended to be positively related to age (P &lt; 0.06). CONCLUSIONS: A clinically important functional benefit of obesity reduction was confirmed in both study groups, with no significant group effect. Our findings of racial differences in response to the intervention and a potential influence of participant age lend support for further studies sufficiently powered to explore the interaction of race and age with functional responses to obesity reduction in women. This trial was registered at clinicaltrials.gov as NCT02033655