Effects of strength training on specific strength and muscle protein quality control in frail elderly

With aging, the loss of muscle strength exceeds the loss of muscle mass. Specific strength, defined as strength normalized to the cross-sectional area of a muscle or muscle group, declines accordingly. A reduced voluntary activation level may explain some of the decline in specific strength, but also decreased muscle quality appears to be involved. Autophagy is responsible for the degradation of dysfunctional proteins and organelles in muscle cells, and studies in rodents suggest that autophagy is impaired with aging. Whether or not autophagy is impaired with aging also in humans, and whether a possible decline in autophagic activity contributes to the reduction in muscle quality, remains to be investigated. Contrary to aging, specific strength increases following a period of strength training, and this is particularly clear in frail elderly. However, the relative contribution from changes in activation level and muscle quality is not known. Moreover, whether or not changes in protein quality control systems contribute to improved muscle quality has not been investigated. The main goal of this thesis was to investigate the effect of heavy load strength training on a broad number of factors related to specific strength in pre-frail and frail elderly. In addition, a cross-sectional study was conducted to assess if autophagy is different in elderly and frail compared to healthy and young humans. In total, 93 men and women (17 young, 76 old) were included in the studies. In the cross-sectional study, the following four groups were compared: Young, old non-frail, old pre-frail and old frail. Specific strength was measured as maximal isometric knee extension torque (MVC) normalized to leg lean mass assessed by DXA. Muscle biopsies were obtained from the vastus lateralis muscle, and analyzed for proteins related to muscle protein synthesis (p70S6K, 4E-BP1, eEF2), autophagy (p62, LC3-I, LC3-II) and cellular stress (heat shock proteins; Hsp70, αB-crystallin) by western blot. In the main intervention study, pre-frail and frail elderly underwent heavy load strength training twice weekly for ten weeks. Specific strength was measured as knee extension MVC normalized to cross-sectional area (CSA) of the quadriceps femoris muscles, assessed by computed tomography (CT). Voluntary activation level was assessed by the twitch interpolation technique, intermuscular adipose tissue (IMAT) and muscle density by CT, and intramyocellular lipids (IMCL) by Oil Red O staining on muscle biopsy sections. In addition, single fiber specific tension was investigated, and the biopsies were also analyzed for proteins related to muscle protein synthesis, autophagy and cellular stress. Functional capacity was assessed by five times chair rise time and gait velocity. In the cross-sectional study, specific strength was lowest in old frail subjects. No between-group differences were observed for p70S6K, 4E-BP1, eEF2 or p62, whereas the levels of LC3-I, LC3-II and certain heat shock proteins (HSPs) were higher in the elderly subjects. Higher levels of LC3-I and LC3-II might reflect attenuated fusion of autophagosomes and lysosomes, and higher levels of HSPs might indicate increased levels of denatured and dysfunctional proteins. In the intervention study, a strong correlation was observed between quadriceps femoris CSA and knee extension MVC at baseline (r = 0.89, P < 0.01). The training intervention did not elicit changes in activation level, IMAT, IMCL or single fiber specific tension. An increase in muscle density was observed, but increased density was not correlated with changes in IMCL content or single fiber specific tension. The intervention had limited effects on autophagy proteins and HSPs. In contrast to our hypothesis, the increase in quadriceps femoris CSA (7%) corresponded well with the improvements in knee extension MVC (7%). The training intervention improved habitual and maximal gait velocity, but not five times chair rise time. In contrast to several previous studies, our findings suggest that even in pre-frail and frail elderly, most of the variation in muscle strength is explained by differences in muscle cross-sectional area. Moreover, the training-induced increase in muscle strength was primarily due to increased muscle quantity, not quality in our study. Nevertheless, we found indications of impaired autophagy and higher cellular stress in elderly and frail individuals compared to young and healthy individuals. Furthermore, specific strength was lowest in the elderly and frail, and within the elderly there was a correlation between markers of autophagy and specific strength, supporting a possible relation between impaired protein quality control and reduced muscle quality. Altogether, impaired autophagy may play a role in the age-associated decline in specific strength, but muscle mass seems to be the most important determinant of muscle strength and function even in old and frail individuals. It is too early to conclude that strength training does not affect protein quality control systems in this population, and it is possible that a higher frequency or longer duration of training is required to elicit greater changes

Strength training and protein supplementation improve muscle mass, strength, and function in mobility-limited older adults: a randomized controlled trial

Background Adaptation to strength training in very old mobility-limited individuals is not fully characterized. Therefore, the aim of this study was to perform a thorough investigation of the adaptation to a lower body strength training regime in this population, with particular emphasis on the relationship between changes in selected variables.MethodsTwenty-two mobility-limited older men and women (85 ± 6 years) were randomized to either a group performing 30 min of heavy-load strength training three times a week, with daily protein supplementation, for 10 weeks (ST), or a control group. End points were leg lean mass assessed by DXA, muscle thickness assessed by ultrasound, isometric and dynamic strength, rate of torque development, and functional capacity.ResultsLeg lean mass increased from baseline in ST (0.7 ± 0.3 kg), along with increased thickness of vastus lateralis (4.4 ± 3.2%), rectus femoris (6.7 ± 5.1%), and vastus intermedius (5.8 ± 5.9%). The hypertrophy was accompanied by improved knee extensor strength (20–23%) and functional performance (7–11%). In ST, neither the change in leg lean mass nor muscle thickness correlated with changes in muscle strength. However, a strong correlation was observed between the change in isometric strength and gait velocity (r = 0.70).ConclusionsThe mismatch between gains in muscle size and strength suggests that muscle quality-related adaptations con-tributed to the increases in strength. The correlations observed between improvements in strength and function suggests that interventions eliciting large improvements in strength may also be superior in terms of functional gains in this population

Strength training and protein supplementation improve muscle mass, strength, and function in mobility-limited older adults: a randomized controlled trial

Background Adaptation to strength training in very old mobility-limited individuals is not fully characterized. Therefore, the aim of this study was to perform a thorough investigation of the adaptation to a lower body strength training regime in this population, with particular emphasis on the relationship between changes in selected variables.MethodsTwenty-two mobility-limited older men and women (85 ± 6 years) were randomized to either a group performing 30 min of heavy-load strength training three times a week, with daily protein supplementation, for 10 weeks (ST), or a control group. End points were leg lean mass assessed by DXA, muscle thickness assessed by ultrasound, isometric and dynamic strength, rate of torque development, and functional capacity.ResultsLeg lean mass increased from baseline in ST (0.7 ± 0.3 kg), along with increased thickness of vastus lateralis (4.4 ± 3.2%), rectus femoris (6.7 ± 5.1%), and vastus intermedius (5.8 ± 5.9%). The hypertrophy was accompanied by improved knee extensor strength (20–23%) and functional performance (7–11%). In ST, neither the change in leg lean mass nor muscle thickness correlated with changes in muscle strength. However, a strong correlation was observed between the change in isometric strength and gait velocity (r = 0.70).ConclusionsThe mismatch between gains in muscle size and strength suggests that muscle quality-related adaptations con-tributed to the increases in strength. The correlations observed between improvements in strength and function suggests that interventions eliciting large improvements in strength may also be superior in terms of functional gains in this population

Transitional justice in practice : truth commissions and policies of victim reparations

Over the years, truth commissions have become an appealing mechnism for dealing with large scale human rights violations. One of the reasons for this is that they avail more opportunities for dealing with the many shades of grey that characterise most conflicts. The mandates have also evolved beyond establishing the truth. It is now common for truth commissions to propose measures or reparations programmes for victims as part of its recommendations. However, considering that truth commissions are temporary establishments with limited time frames and restrictive mandates, what therefore is the future of the recommendations they make in the reports? To further compound this situation, there is often a considerably diminished interest in the issues they raise in the post truth commission phase. The objective of this research is to study the recommendations relating to reparations that truth commissions have issued. It examines how different stakeholders respond to the recommendations and the frameworks that have been set up (or not) to follow-up and implement specific recommendations. Two case studies, Sierra Leone Truth and Reconciliation Commission and the Ghana National Reconciliation Commission are selected. Whereas these two cases both recommended reparations for victims, different approaches for the follow-up were instituted, both in the reports and during the post truth commission phase. How is this related to the actual realities on the ground with regard to victims’ reparations? This research takes on four major issues in relation to truth commissions and reparations: the inclusion or omission of reparations in the mandate of truth commissions; the content of the recommendations (what reparation, for whom and to whom); the follow-up of the recommendations (agencies and frameworks) and, relevance of truth commissions in making recommendations for victims’ reparations. The research describes the different contexts for the inclusion of reparations within truth commissions and strategies for their implementation, and to this end, it proposes a model for studying the follow-up of recommendations on reparations made by truth commissions.BRIEF TABLE OF CONTENTS MEMBERS OF THE EXAMINATION COMMITTEE.................... iii ACKNOWLEDGEMENTS.......................................... v Abstract................................................ vii BRIEF TABLE OF CONTENTS.................................. xi DETAILED TABLE OF CONTENTS............................. xiii LIST OF FIGURES......................................... xxv LIST OF TABLES.......................................... xxv LIST OF ABBREVIATIONS................................. xxvii GENERAL INTRODUCTION...................................... 3 PART I. SETTING OF THE STUDY.............................. 9 CHAPTER 1. BACKGROUND AND METHODS........................ 11 PART II. THEORETICAL CONSTRUCTIONS....................... 43 CHAPTER 3 IMPLEMENTATION OF RECOMMENDATIONS: POST-TRUTH COMMISSION............................................... 73 CHAPTER 4. CRIMINOLOGY, TRUTH COMMISSIONS AND REPARATION 95 PART III. OVERVIEW OF THE SELECTED CASES ............... 115 CHAPTER 5: GHANA: “WAS THERE A TRC IN GHANA?”........... 117 CHAPTER 6: SIERRA LEONE: LONG ROAD TO REPARATION ........147 CHAPTER 7: SYNTHESISING THE TWO CASES................... 183 PART IV. RESULTS OF THE EMPIRICAL STUDY................. 195 CHAPTER 8. GHANA: “IT’S NOT PERFECT, BUT IT IS BETTER THAN NONE.” ................................................. 197 CHAPTER 9. SIERRA LEONE: IMPROVISING WITH LIMITED RESOURCES .........................................................253 CHAPTER 10. A GENERAL NOTE ON THE EMPIRICAL STUDY....... 325 PART V: TOWARDS A STUDY OF IMPLEMENTATION .............. 335 CHAPTER 11: UNDERSTANDING IMPLEMENTATION RESEARCH....... 337 CHAPTER 12: FRAMEWORK FOR STUDYING IMPLEMENTATION FOLLOWING TRUTH COMMISSION RECOMMENDATIONS........................ 355 GENERAL CONCLUSION...................................... 377 RECOMMENDATIONS......................................... 389 REFERENCES.............................................. 393nrpages: 434status: publishe

Patient and public involvement in health research in Norway: a survey among researchers and patient organisations

Abstract Background Patient and public involvement (PPI) in health research may improve both the relevance and quality of the research. There is however a lack of research investigating the experiences, attitudes and barriers towards PPI in clinical research in Norway. The Norwegian Clinical Research Infrastructure Network therefore conducted a survey among researchers and PPI contributors aiming to investigate experiences with PPI and identify current challenges for successful involvement. Methods Two survey questionnaires were developed and distributed in October and November 2021. The survey targeting 1185 researchers was distributed from the research administrative system in the Regional Health Trusts. The survey targeting PPI contributors was distributed through Norwegian patient organisations, regional and national competence centers. Results The response rate was 30% among researchers and was unobtainable from PPI contributors due to the survey distribution strategy. PPI was most frequently used in the planning and conduct of the studies, and less utilized in dissemination and implementation of results. Both researchers and user representatives were generally positive to PPI, and agreed that PPI might be more useful in clinical research than in underpinning research. Researchers and PPI contributors who reported that roles and expectations were clarified in advance, were more likely to experience a common understanding of roles and responsibilities in the research project. Both groups pointed to the importance of earmarked funding for PPI activities. There was a demand for a closer collaboration between researchers and patient organisations to develop accessible tools and effective models for PPI in health research. Conclusions Surveys among clinical researchers and PPI contributors indicate overall positive attitudes towards PPI in clinical research. However, more resources, such as budget, time, and accessible tools, are needed. Clarifying roles and expectations, and creating new PPI models under resource constraints can enhance its effectiveness. PPI is underutilized in disseminating and implementing research results, presenting an opportunity for improving healthcare outcomes

The effects of cold water immersion and active recovery on molecular factors that regulate growth and remodeling of skeletal muscle after resistance exercise

Regular postexercise cooling attenuates muscle hypertrophy, yet its effects on the key molecular factors that regulate muscle growth and remodeling are not well characterized. In the present study, nine men completed two sessions of single-leg resistance exercise on separate days. On 1 day, they sat in cold water (10°C) up to their waist for 10 min after exercise. On the other day, they exercised at a low intensity for 10 min after exercise. Muscle biopsies were collected from the exercised leg before, 2, 24, and 48 h after exercise in both trials. These muscle samples were analyzed to evaluate changes in genes and proteins involved in muscle growth and remodeling. Muscle-specific RING finger 1 mRNA increased at 2 h after both trials (P < 0.05), while insulin-like growth factor (IGF)-1 Ec, IGF-1 receptor, growth arrest and DNA damage-inducible protein 45, collagen type I alpha chain A, collagen type III alpha chain 1, laminin and tissue inhibitor of metallopeptidase 1 mRNA increased 24−48 h after both trials (P < 0.05). By contrast, atrogin-1 mRNA decreased at all time points after both trials (P < 0.05). Protein expression of tenascin C increased 2 h after the active recovery trial (P < 0.05), whereas FoxO3a protein expression decreased after both trials (P < 0.05). Myostatin mRNA and ubiquitin protein expression did not change after either trial. These responses were not significantly different between the trials. The present findings suggest that regular cold water immersion attenuates muscle hypertrophy independently of changes in factors that regulate myogenesis, proteolysis and extracellular matrix remodeling in muscle after exercise.</p

The Effects of Cold Water Immersion and Active Recovery on Molecular Factors That Regulate Growth and Remodeling of Skeletal Muscle After Resistance Exercise

Regular postexercise cooling attenuates muscle hypertrophy, yet its effects on the key molecular factors that regulate muscle growth and remodeling are not well characterized. In the present study, nine men completed two sessions of single-leg resistance exercise on separate days. On 1 day, they sat in cold water (10°C) up to their waist for 10 min after exercise. On the other day, they exercised at a low intensity for 10 min after exercise. Muscle biopsies were collected from the exercised leg before, 2, 24, and 48 h after exercise in both trials. These muscle samples were analyzed to evaluate changes in genes and proteins involved in muscle growth and remodeling. Muscle-specific RING finger 1 mRNA increased at 2 h after both trials (P < 0.05), while insulin-like growth factor (IGF)-1 Ec, IGF-1 receptor, growth arrest and DNA damage-inducible protein 45, collagen type I alpha chain A, collagen type III alpha chain 1, laminin and tissue inhibitor of metallopeptidase 1 mRNA increased 24−48 h after both trials (P < 0.05). By contrast, atrogin-1 mRNA decreased at all time points after both trials (P < 0.05). Protein expression of tenascin C increased 2 h after the active recovery trial (P < 0.05), whereas FoxO3a protein expression decreased after both trials (P < 0.05). Myostatin mRNA and ubiquitin protein expression did not change after either trial. These responses were not significantly different between the trials. The present findings suggest that regular cold water immersion attenuates muscle hypertrophy independently of changes in factors that regulate myogenesis, proteolysis and extracellular matrix remodeling in muscle after exercise

Native whey protein with high levels of leucine results in similar post-exercise muscular anabolic responses as regular whey protein: a randomized controlled trial

Abstract Background Protein intake is essential to maximally stimulate muscle protein synthesis, and the amino acid leucine seems to possess a superior effect on muscle protein synthesis compared to other amino acids. Native whey has higher leucine content and thus a potentially greater anabolic effect on muscle than regular whey (WPC-80). This study compared the acute anabolic effects of ingesting 2 × 20 g of native whey protein, WPC-80 or milk protein after a resistance exercise session. Methods A total of 24 young resistance trained men and women took part in this double blind, randomized, partial crossover, controlled study. Participants received either WPC-80 and native whey (n = 10), in a crossover design, or milk (n = 12). Supplements were ingested immediately (20 g) and two hours after (20 g) a bout of heavy-load lower body resistance exercise. Blood samples and muscle biopsies were collected to measure plasma concentrations of amino acids by gas-chromatography mass spectrometry, muscle phosphorylation of p70S6K, 4E–BP1 and eEF-2 by immunoblotting, and mixed muscle protein synthesis by use of [2H5]phenylalanine-infusion, gas-chromatography mass spectrometry and isotope-ratio mass spectrometry. Being the main comparison, differences between native whey and WPC-80 were analysed by a one-way ANOVA and comparisons between the whey supplements and milk were analysed by a two-way ANOVA. Results Native whey increased blood leucine concentrations more than WPC-80 and milk (P < 0.05). Native whey ingestion induced a greater phosphorylation of p70S6K than milk 180 min after exercise (P = 0.03). Muscle protein synthesis rates increased 1–3 h hours after exercise with WPC-80 (0.119%), and 1–5 h after exercise with native whey (0.112%). Muscle protein synthesis rates were higher 1–5 h after exercise with native whey than with milk (0.112% vs. 0.064, P = 0.023). Conclusions Despite higher-magnitude increases in blood leucine concentrations with native whey, it was not superior to WPC-80 concerning effect on muscle protein synthesis and phosphorylation of p70S6K during a 5-h post-exercise period. Native whey increased phosphorylation of p70S6K and muscle protein synthesis rates to a greater extent than milk during the 5-h post exercise period. Trial registration This study was retrospectively registered at clinicaltrials.gov as NCT02968888

The effects of cold water immersion and active recovery on inflammation and cell stress responses in human skeletal muscle after resistance exercise

Cold water immersion and active recovery are common post‐exercise recovery treatments. However, little is known about whether these treatments influence inflammation and cellular stress in human skeletal muscle after exercise. We compared the effects of cold water immersion versus active recovery on inflammatory cells, pro‐inflammatory cytokines, neurotrophins and heat shock proteins (HSPs) in skeletal muscle after intense resistance exercise. Nine active men performed unilateral lower‐body resistance exercise on separate days, at least 1 week apart. On one day, they immersed their lower body in cold water (10°C) for 10 min after exercise. On the other day, they cycled at a low intensity for 10 min after exercise. Muscle biopsies were collected from the exercised leg before, 2, 24 and 48 h after exercise in both trials. Exercise increased intramuscular neutrophil and macrophage counts, MAC1 and CD163 mRNA expression (P IL1β, TNF, IL6, CCL2, CCL4, CXCL2, IL8 and LIF mRNA expression (P NGF and GDNF mRNA increased after exercise (P P < 0.05). This response was accompanied by increases in the cytoskeletal protein content of αB‐crystallin and the percentage of type II fibres stained for αB‐crystallin. Changes in inflammatory cells, cytokines, neurotrophins and HSPs did not differ significantly between the recovery treatments. These findings indicate that cold water immersion is no more effective than active recovery for reducing inflammation or cellular stress in muscle after a bout of resistance exercise

Native whey induces similar post exercise muscle anabolic responses as regular whey, despite greater leucinemia, in elderly individuals

Objective: Elderly muscle seems less sensitive to the anabolic stimulus of a meal. Changes in blood concentrations of leucine are suggested as one important trigger of the anabolic response in muscle. The aim of this study was to investigate whether native whey protein, containing high amounts of leucine, may be a more potent stimulator of muscle protein synthesis (MPS) in elderly than regular whey protein (WPC-80) or milk. Design: Randomized controlled partial crossover. Setting: Norwegian School of Sport Sciences. Participants: 21 healthy elderly men and women (≥70 years). Intervention: Participants received either 20 g of WPC-80 and native whey (n = 11) on separate days in a crossover design, or milk (n = 10). Supplements were ingested immediately and two hours after a bout of lower body heavy-load resistance exercise. Measurements: Blood samples and muscle biopsies were collected to measure blood concentrations of amino acids by gas-chromatography mass spectrometry (GCMS), phosphorylation of p70S6K, 4E-BP1 and eEF-2 by immunoblotting and mixed muscle fractional synthetic rate (FSR) by use of [2H5]phenylalanine-infusion, GCMS and isotope-ratio mass spectrometry. Results: Native whey increased blood leucine concentrations more than WPC-80 (P < 0.05), but not p70S6K phosphorylation or mixed muscle FSR. Both whey supplements increased blood leucine concentrations (P < 0.01) and P70S6K phosphorylation more than milk (P = 0.014). Native whey reached higher mixed muscle FSR values than milk (P = 0.026) 1-3h after exercise. Conclusions: Despite greater increases in blood leucine concentrations than WPC-80 and milk, native whey was only superior to milk concerning increases in MPS and phosphorylation of P70S6K during a 5-hour post-exercise period in elderly individuals