Denervation Causes Fiber Atrophy and Myosin Heavy Chain Co-Expression in Senescent Skeletal Muscle

Although denervation has long been implicated in aging muscle, the degree to which it is causes the fiber atrophy seen in aging muscle is unknown. To address this question, we quantified motoneuron soma counts in the lumbar spinal cord using choline acetyl transferase immunhistochemistry and quantified the size of denervated versus innervated muscle fibers in the gastrocnemius muscle using the in situ expression of the denervation-specific sodium channel, Nav1.5, in young adult (YA) and senescent (SEN) rats. To gain insights into the mechanisms driving myofiber atrophy, we also examined the myofiber expression of the two primary ubiquitin ligases necessary for muscle atrophy (MAFbx, MuRF1). MN soma number in lumbar spinal cord declined 27% between YA (638±34 MNs×mm−1) and SEN (469±13 MNs×mm−1). Nav1.5 positive fibers (1548±70 μm2) were 35% smaller than Nav1.5 negative fibers (2367±78 μm2; P<0.05) in SEN muscle, whereas Nav1.5 negative fibers in SEN were only 7% smaller than fibers in YA (2553±33 μm2; P<0.05) where no Nav1.5 labeling was seen, suggesting denervation is the primary cause of aging myofiber atrophy. Nav1.5 positive fibers had higher levels of MAFbx and MuRF1 (P<0.05), consistent with involvement of the proteasome proteolytic pathway in the atrophy of denervated muscle fibers in aging muscle. In summary, our study provides the first quantitative assessment of the contribution of denervation to myofiber atrophy in aging muscle, suggesting it explains the majority of the atrophy we observed. This striking result suggests a renewed focus should be placed on denervation in seeking understanding of the causes of and treatments for aging muscle atrophy

Strategies to Address Misestimation of Energy Intake Based on Self-Report Dietary Consumption in Examining Associations Between Dietary Patterns and Cancer Risk

Solbak, N. M., Al Rajabi, A., Akawung, A. K., Lo Siou, G., Kirkpatrick, S. I., & Robson, P. J. (2019). Strategies to Address Misestimation of Energy Intake Based on Self-Report Dietary Consumption in Examining Associations Between Dietary Patterns and Cancer Risk. Nutrients, 11(11), 2614. https://doi.org/10.3390/nu11112614The objective of this study was to determine the influence of strategies of handling misestimation of energy intake (EI) on observed associations between dietary patterns and cancer risk. Data from Alberta’s Tomorrow Project participants (n = 9,847 men and 16,241 women) were linked to the Alberta Cancer Registry. The revised-Goldberg method was used to characterize EI misestimation. Four strategies assessed the influence of EI misestimation: Retaining individuals with EI misestimation in the cluster analysis (Inclusion), excluding before (ExBefore) or after cluster analysis (ExAfter), or reassigning into ExBefore clusters using the nearest neighbor method (InclusionNN). Misestimation of EI affected approximately 50% of participants. Cluster analysis identified three patterns: Healthy, Meats/Pizza and Sweets/Dairy. Cox proportional hazard regression models assessed associations between the risk of cancer and dietary patterns. Among men, no significant associations (based on an often-used threshold of p < 0.05) between dietary patterns and cancer risk were observed. In women, significant associations were observed between the Sweets/Dairy and Meats/Pizza patterns and all cancer risk in the ExBefore (HR (95% CI): 1.28 (1.04–1.58)) and InclusionNN (HR (95% CI): 1.14 (1.00–1.30)), respectively. Thus, strategies to address misestimation of EI can influence associations between dietary patterns and disease outcomes. Identifying optimal approaches for addressing EI misestimation, for example, by leveraging biomarker-based studies could improve our ability to characterize diet-disease associations.Funder 1, Alberta’s Tomorrow Project is funded by the Alberta Cancer Foundation || Funder 2, the Canadian Partnership Against Cancer|| Funder 3, the Alberta Cancer Prevention Legacy Fund (administered by the Government of Alberta) || Funder 4, the University of Toronto and substantial in-kind funding from Alberta Health Services. Although funding has been provided by several organizations, the analyses and interpretation of the data presented in this paper are those of the authors alon

Evaluating the feasibility of administering a combination of online dietary assessment tools in a cohort of adults in Alberta, Canada

Purpose: Evidence suggests that combining tools, such as 24-hour recalls and food frequency questionnaires, may allow more accurate assessment of diet in epidemiologic studies. Webbased technology should make this approach more feasible than in the past, but it is important to explore response rates and acceptability of such an approach in real-world settings. We sought to determine the feasibility of using a combination of online tools (Automated SelfAdministered 24-hour (ASA24) Dietary Assessment Tool and Diet History Questionnaire-II (DHQ-II)) in a sub-set of participants in Alberta’s Tomorrow Project (ATP); a prospective cohort of 55,000 adults >35y in Alberta, Canada. Methods: Invitations to the feasibility study were mailed to 550 ATP participants. Those who consented (n=331) were asked to complete a health questionnaire, four ASA24 recalls (approximately three weeks apart over a four month period, with staggered start dates between June and December 2016), followed by the DHQ-II, and an evaluation survey. Results: The majority of participants [mean (SD) age =57.1 (10.1)] were women (70.7%), urban residents (84.8%) and non-smokers (95.7%). Of the 229 participants who completed at least one ASA24, roughly equal proportions completed one (24.8%), two (24.5%), three (24.5%) and four recalls (26.2%). One third (n=102) of consenting participants did not respond to any ASA24 recall requests, with “lack of time” given as the primary reason. Only 41% of consenting participants (n=136) completed the DHQ-II; of these, 40% (n=55) completed all four recalls. Median (25th-75th percentile) completion times were 46 (26-64) minutes for the first ASA24 recall and 50 (40-90) minutes for the DHQ-II. Conclusions: Over half of participants completed at least two or more ASA24 recalls, and those who completed a greater number of recalls also completed the DHQ-II, demonstrating that the approach is feasible in the ATP cohort. However, response rates may be sensitive to the timing and frequency of recall administration. Future investigations will (i) evaluate the dietary data collected from each tool; (ii) explore methods of combining the data to optimize assessment of diet in the cohort, while accounting for the fact that not all participants will complete the entire dietary assessment protocol

Denervation Causes Fiber Atrophy and Myosin Heavy Chain Co-Expression in Senescent Skeletal Muscle

Although denervation has long been implicated in aging muscle, the degree to which it is causes the fiber atrophy seen in aging muscle is unknown. To address this question, we quantified motoneuron soma counts in the lumbar spinal cord using choline acetyl transferase immunhistochemistry and quantified the size of denervated versus innervated muscle fibers in the gastrocnemius muscle using the in situ expression of the denervation-specific sodium channel, Nav1.5, in young adult (YA) and senescent (SEN) rats. To gain insights into the mechanisms driving myofiber atrophy, we also examined the myofiber expression of the two primary ubiquitin ligases necessary for muscle atrophy (MAFbx, MuRF1). MN soma number in lumbar spinal cord declined 27% between YA (638±34 MNs×mm−1) and SEN (469±13 MNs×mm−1). Nav1.5 positive fibers (1548±70 μm2) were 35% smaller than Nav1.5 negative fibers (2367±78 μm2; P<0.05) in SEN muscle, whereas Nav1.5 negative fibers in SEN were only 7% smaller than fibers in YA (2553±33 μm2; P<0.05) where no Nav1.5 labeling was seen, suggesting denervation is the primary cause of aging myofiber atrophy. Nav1.5 positive fibers had higher levels of MAFbx and MuRF1 (P<0.05), consistent with involvement of the proteasome proteolytic pathway in the atrophy of denervated muscle fibers in aging muscle. In summary, our study provides the first quantitative assessment of the contribution of denervation to myofiber atrophy in aging muscle, suggesting it explains the majority of the atrophy we observed. This striking result suggests a renewed focus should be placed on denervation in seeking understanding of the causes of and treatments for aging muscle atrophy

Administering a combination of online dietary assessment tools, the Automated Self-Administered 24-Hour Dietary Assessment Tool, and Diet History Questionnaire II, in a cohort of adults in Alberta\u27s Tomorrow Project

Background: Evidence suggests that combining tools that gather short- and long-term dietary data may be the optimal approach for the assessment of diet–disease associations in epidemiologic studies. Online technology can reduce the associated burdens for researchers and participants, but feasibility must be demonstrated in real-world settings before wide-scale implementation. Objective: The objective of this study was to determine the feasibility and acceptability of combining web-based tools (the Automated Self-Administered 24-hour Dietary Assessment Tool [ASA24-2016] and the past-year Diet History Questionnaire II [DHQ-II]) in a subset of participants in Alberta\u27s Tomorrow Project, a prospective cohort. Design: For this feasibility study, invitations were mailed to 550 randomly selected individuals enrolled in Alberta\u27s Tomorrow Project. Consented participants (n = 331) were asked to complete a brief sociodemographic and health questionnaire, four ASA24-2016 recalls, the DHQ-II, and an evaluation survey. Participants/setting: The study was conducted from March 2016 to December 2016 in Alberta, Canada. The majority of participants, mean age (SD) = 57.4 (9.8) years, were women (70.7%), urban residents (85.5%), and nonsmokers (95.7%). Main outcome measures: Primary outcomes were number of ASA24-2016 recalls completed, response rate of DHQ-II completion, and time to complete each assessment. Statistical analyses: The Wilcoxon signed rank sum test was used to assess differences in completion time. Results: One-third (n = 102) of consenting participants did not complete any ASA24-2016 recalls. The primary reason to withdraw from the feasibility study was a lack of time. Among consenting participants, 51.9% (n = 172), 41.1% (n = 136), and 36.5% (n = 121) completed at least two ASA24-2016 recalls, the DHQ-II, and at least two ASA24-2016 recalls plus the DHQ-II, respectively. Median (25th to 75th percentile) completion times for participants who completed all recalls were 39 minutes (25 to 53 minutes) for the first ASA24-2016 recall and 60 minutes (40 to 90 minutes) for the DHQ-II. Conclusions: Findings indicate combining multiple ASA24-2016 recalls and the DHQ-II is feasible in this subset of Alberta\u27s Tomorrow Project participants. However, optimal response rates may be contingent on providing participant support. Completion may also be sensitive to timing and frequency of recall administration

The effect of different methods to identify, and scenarios used to address energy intake misestimation on dietary patterns derived by cluster analysis

Background: All self-reported dietary intake data are characterized by measurement error, and validation studies indicate that the estimation of energy intake (EI) is particularly affected. Methods: Using self-reported food frequency and physical activity data from Alberta’s Tomorrow Project participants (n = 9847 men 16,241 women), we compared the revised-Goldberg and the predicted total energy expenditure methods in their ability to identify misreporters of EI. We also compared dietary patterns derived by k-means clustering under different scenarios where misreporters are included in the cluster analysis (Inclusion); excluded prior to completing the cluster analysis (ExBefore); excluded after completing the cluster analysis (ExAfter); and finally, excluded before the cluster analysis but added to the ExBefore cluster solution using the nearest neighbor method (InclusionNN). Results: The predicted total energy expenditure method identified a significantly higher proportion of participants as EI misreporters compared to the revised-Goldberg method (50% vs. 47%, p \u3c 0.0001). k-means cluster analysis identified 3 dietary patterns: Healthy, Meats/Pizza and Sweets/Dairy. Among both men and women, participants assigned to dietary patterns changed substantially between ExBefore and ExAfter and also between the Inclusion and InclusionNN scenarios (Hubert and Arabie’s adjusted Rand Index, Kappa and Cramer’s V statistics \u3c 0.8). Conclusions: Different scenarios used to account for EI misreporters influenced cluster analysis and hence the composition of the dietary patterns. Continued efforts are needed to explore and validate methods and their ability to identify and mitigate the impact of EI misestimation in nutritional epidemiology

Patterns and predictors of adherence to colorectal cancer screening recommendations in Alberta’s Tomorrow Project participants stratified by risk

Abstract Background Colorectal cancer (CRC) screening is an important modifiable behaviour for cancer control. Regular screening, following recommendations for the type, timing and frequency based on personal CRC risk, contributes to earlier detection and increases likelihood of successful treatment. Methods To determine adherence to screening recommendations in a large provincial cohort of adults, participants in Alberta’s Tomorrow Project (n = 9641) were stratified based on increasing level of CRC risk: age (Age-only), family history of CRC (FamilyHx), personal history of bowel conditions (PersonalHx), or both (Family/PersonalHx) using self-reported information from questionnaires. Provincial and national guidelines for timing and frequency of screening tests were used to determine if participants were up-to-date based on their CRC risk. Screening status was compared between enrollment (2000–2006) and follow-up (2008) to determine screening pattern over time. Results The majority of participants (77%) fell into the average risk Age-only strata. Only a third of this strata were up-to-date for screening at baseline, but the proportion increased across the higher risk strata, with > 90% of the highest risk Family/PersonalHx strata up-to-date at baseline. There was also a lower proportion (< 25%) of the Age-only group who were regular screeners over time compared to the higher risk strata, though age, higher income and uptake of other screening tests (e.g. mammography) were associated with a greater likelihood of regular screening in multinomial logistic regression. Conclusions The low (< 50%) adherence to regular CRC screening in average and moderate risk strata highlights the need to further explore barriers to uptake of screening across different risk profiles

Spinal cord motoneuron counts.

<p>A: Photomicrograph of choline acetyl transferase labeled cross-sections of the spinal cord from a young adult rat and B: senescent rat (scale bar = 400 µm). Insets for both panels are higher power images showing motoneuron soma (arrows) (scale bar = 40 µm). C: mean motoneuron counts for young adult (YA) and senescent (SEN) rats. *P<0.05 versus YA.</p

Fiber type changes with aging.

<p>Photomicrographs of serial sections labeled for myosin heavy chain (MHC) slow (A,C) and MHC fast (B,D) within the red region of gastrocnemius muscle from a young adult (A,B) and senescent (C,D) rat. In these images 1 denotes a MHCs fiber, 2 denotes a MHCf fiber, and 3 denotes a fiber co-expressing both MHCs and MHCf. Scale bar is 50 µm.</p