Multi-organ Responses to CHronic Physical Activity and INactivity (CHAIN)

Concurrent Multi-organ Responses to CHronic Physical Activity and INactivity Intervention, to Increase Research Discovery in Human Health and Wellbeing

Life expectancy has been increasing for the last 150 years, but the maintenance of health has not kept pace with increased lifespan, and on average, UK adults spend the last decade of life in poor-health, with major consequences for society and the individual.

Persistent physical inactivity is thought to be a key contributing factor to the risk of poor health and functional decline occurring in middle-aged and older adults. It is therefore concerning that most middle-aged adults spend >8hrs/day being sedentary, with average step count of 3000-4000 steps/day.

To be able to holistically assess the effectiveness of future strategies to address age-related decline in health, and devise public health messages to help individuals reach older age in better health, it is essential that the complex physiological effects that activity and inactivity have across biological systems are characterised.

The goal of this intervention study is to compare the impact of physical activity and inactivity on body functioning. Twenty moderately active participants will decrease their physical activity for six months to match the average amount carried out by middle-aged people in the UK. They will then undertake 3-months of reconditioning training to restore their fitness. In addition, twenty sedentary participants will increase their physical activity to UK recommended levels for six months.

Before and at points during the intervention period, participants will be asked to make some measurements at home and attend the University of Nottingham to have multiple assessments made. These include;

• fitness, muscle strength and function tests,
• completion of questionnaires and computer-based brain puzzles
• having muscle and fat tissue biopsies and blood samples taken.
• The study also involves having MRI scans.

This 5-year study will commence in January 2024, with participant recruitment starting in March 2024 and finishing in May 2027.

Study Overview

• Status: Recruiting
• Conditions: Metabolic Syndrome; Sedentary Behavior; Age-related Cognitive Decline; Age-Related Sarcopenia
• Intervention / Treatment: Behavioral: Decreased Physical Activity; Behavioral: Increased Physical activity

Detailed Description

This is a parallel design study comparing the impact of physical activity and inactivity on the way the body functions, to understand the mechanisms (including the inter-relationship between tissues and organs) by which lifestyle behaviours may effect health and wellbeing in later life. In particular, the mechanisms by which inactivity results in long term poor health is not well understood, and has rarely been studied in an integrated way in people. However, initial research indicates that the physiology of being inactive is not simply the reverse of being active. To enable effective treatments and public health advice to be devised so that more adults reach old age in better health, and maintain a good quality of life for a greater proportion of their older age, it is important that the impact of physical inactivity on the way the body functions is better understood. Therefore, twenty participants who are moderately, but not highly active will be asked to decrease their physical activity for six months to match the average exercise levels of middle-aged people in the United Kingdom (UK). This will require them to increase their daily sitting time to 7 hours a day and reduce their step count to <4500 steps per day. At the end of the 6-months they will undertake 3-months of supervised reconditioning training to restore their fitness.

In addition, twenty participants who currently have low physical activity levels will be asked to increase their physical activity to UK recommended levels by attending the Medical School at Queen's Medical Centre, Nottingham, three times a week for six months to undertake a supervised exercise program.

Before and during the 6-month period (at weeks 6, 12, 18 and 24) participants will be asked to make some measurements at home (physical activity levels, dietary intake) and attend the University of Nottingham over 4 days to have multiple assessments made. These include: height; weight; body composition (body fat and lean tissue); blood pressure; fitness, muscle strength and function; sleep quality, quality of life and wellbeing (questionnaires). The rate of muscle protein breakdown and muscle protein synthesis, blood sugar regulation, and biochemistry of the blood, fat tissue and muscles will be assessed, and to enable this muscle and fat tissue biopsies will be collected and blood samples taken. The study also involves having MRI scans to study the structure and function of the brain and heart, and to determine liver and muscle fat content.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Paul Greenhaff (PI), PhD; Phone Number: +44 (0) 1158230133; Email: paul.greenhaff@nottingham.ac.uk
• Study Contact Backup: Name: Aline Nixon (participant recruitment), BSc; Phone Number: 19105 +44 (0) 115 9515151; Email: aline.nixon@nottingham.ac.uk

Study Locations

• United Kingdom
  • Notts
    • Nottingham, Notts, United Kingdom, NG72UH
      • Recruiting
      • David Greenfield Human Physiology Unit
      • Sub-Investigator: Sue Francis, PhD
      • Sub-Investigator: Liz Simpson, PhD
      • Contact: Sara Brown; Phone Number: +44(0)115 8230434; Email: sara.brown@nottingham.ac.uk
      • Contact: Joanne Mallinson, PhD; Phone Number: +44(0)1158230434; Email: joanne.mallinson@nottingham.ac.uk
      • Principal Investigator: Paul Greenhaff, PhD
      • Sub-Investigator: Joanne Mallinson, PhD
      • Sub-Investigator: Abhishek Sheth, MD
      • Sub-Investigator: Penny Gowland, PhD
      • Sub-Investigator: Rosemary Nicholls, PhD
      • Sub-Investigator: Aline Nixon
      • Sub-Investigator: Sara Brown
      • Sub-Investigator: Donald Peden, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Group 1 ('non-sedentary') self-reporting <6 sedentary hrs/day, not actively involved in exercise training or a regular physical activity regimen (>8,000<10,000 steps/day).
• Group 2 ('sedentary') self-reporting ≥8 waking hrs/day in sedentary activities and/or ≤5,000 steps/day.
• Aged 55-65y.
• Overweight (BMI 25-29.9 kg/m2).
• Waist circumference ≥94cm (males) and ≥80cm (females).
• Willing to alter physical activity levels as instructed for 6 months
• Without neurological or psychiatric diseases, motor or cognitive restrictions
• Ability to give informed consent

Exclusion Criteria:

• Regular medication use that could interfere with measures
• A history, or evidence, of chronic cardiovascular, metabolic, musculoskeletal, renal or respiratory diseases.
• Experiencing 'long-COVID', inflammatory bowel disease or malignancy.
• Uncontrolled hypertension. Stage 1 hypertension (BP ≤160/100mmHg) with no other signs of cardiovascular disease, and blood pressure (BP) managed by routine medication will not be an exclusion.
• People employed in jobs that would preclude reducing step count and night-shift workers.
• Females who are pre/peri-menopausal or on hormone replacement therapy (due to effect of oestrogen fluctuations on primary outcomes and the longitudinal study design).
• Contraindications for MRI.
• Allergy or sensitivity to local anaesthesia, or dressing adhesive

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Inactivity; Participants in this group will reduce their physical activity (increase sitting time to 7hrs/day and decrease step count to <4500/day) for 6 months	Behavioral: Decreased Physical Activity; Physical activity levels will be decreased
Experimental: Activity; Participants in this group will have moderate intensity physical activity levels increased for 6 months, through attending 3x 45 min supervised exercise sessions/week.	Behavioral: Increased Physical activity; Physical activity levels will be increased

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cardiorespiratory fitness (VO2 max)	change in maximal oxygen uptake (continuous incremental bicycle ergometer exercise test with on-line gas analysis) measured every 6 weeks	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Isometric leg strength	Change in Isometric leg strength measured every 6 weeks using CYBEX dynamometer	24 weeks
Change in time to leg fatigue	Change in time taken to induce muscle fatigue measured every 6 weeks using isokinetic knee extensions on a CYBEX dynamometer	24 weeks
Change in incremental area under the curve (iAUC) for blood glucose concentration	Change in 180 minute blood glucose concentration incremental area under the curve measured every 6 weeks during an oral glucose tolerance test.	24 weeks
Change in iAUC for serum insulin concentration	Change in 180-minute serum insulin concentration incremental area under the curve measured every 6 weeks during an oral glucose tolerance test	24 weeks
Change in fasting glucose oxidation rate	Change in glucose oxidation rate (when fasted), measured every 6 weeks using ventilated hood indirect calorimetry	24 weeks
Change in 'fed' glucose oxidation rate	Change in glucose oxidation rate (in the insulin-stimulated 'fed' state), measured every 6 weeks using ventilated hood indirect calorimetry during an oral glucose tolerance test	24 weeks
Change in Short Form Health Survey (SF36) Questionnaire aggregated normalised 'physical' score	Change in 'SF36' Questionnaire aggregated 'physical' score (normalised to UK population) calculated according to standard procedures (min 0, max 100), with higher score indicating better physical wellbeing measured every 6 weeks	24 weeks
Change in Short Form Health Survey (SF36) Questionnaire aggregated and normalised 'mental' score	Change in 'SF36' Questionnaire aggregated 'mental' score (normalised to UK population) calculated according to standard procedures (min 0, max 100), with higher score indicating better mental wellbeing, measured every 6 weeks	24 weeks
Change in World Health Organisation Quality of Life (WHOQoL) score	Change in World Health Organisation Quality of Life Score (measured using the WHOQoL-Bref questionnaire every 6 weeks), (min score 0, max 100), with higher score indicating a better state of health.	24 weeks
Change in Pittsburgh Sleep Quality Index (PSQI)	Change in PSQI score (min score 0, max 21), measured every 6 weeks, with higher score indicating poorer sleep quality	24 weeks
Change in Stroop test; % Accuracy	Change in the percentage of accurate responses, measured every 6 weeks, with higher score indicating better cognitive performance. Minimum value 0%, maximum value 100%	24 weeks
Change in Stroop test; reaction time	Change in the reaction time for responses, measured every 6 weeks, with higher score indicating slower cognitive performance. No minimum or maximum value defined.	24 weeks
Change in four-choice reaction time test; % Accuracy	Change in the percentage of accurate responses, measured every 6 weeks, with higher score indicating better cognitive performance. Minimum value 0%, maximum value 100%	24 weeks
Change in four-choice reaction time test; reaction time	Change in the reaction time for responses, measured every 6 weeks, with higher score indicating slower cognitive performance. No minimum or maximum value defined.	24 weeks
Change in card sort test; % Accuracy	Change in the percentage of accurate responses, measured every 6 weeks, with higher score indicating better cognitive performance. Minimum value 0%, maximum value 100%	24 weeks
Change in card sort test; reaction time	Change in the reaction time for responses, measured every 6 weeks, with higher score indicating slower cognitive performance. No minimum or maximum value defined.	24 weeks
Change in Logical reasoning test; % accuracy	Change in the accuracy of responses, measured every 6 weeks, with higher score indicating better cognitive performance. Minimum value 0%, maximum value 100%	24 weeks
Change in Logical reasoning test; reaction time	Change in the reaction time for responses, measured every 6 weeks, with higher score indicating slower cognitive performance. No minimum or maximum value defined.	24 weeks
Change in serial subtractions test; number of responses in 2 minutes	Change in the number of responses, measured every 6 weeks, with higher score indicating better cognitive performance. minimum number is 0, maximum number is variable dependent on starting value (800-999; randomly selected by computer program) and speed of response.	24 weeks
Change in Corsi blocks test; score	Change in the test score, measured every 6 weeks, with higher score indicating better cognitive performance.Minimum score is 0 and maximum is 15.	24 weeks
Change in Muscle protein synthesis rate	Muscle synthesis protein rate calculated from deuterium incorporation into muscle tissue	24 weeks
Change in Muscle protein breakdown rate	Muscle protein breakdown rate calculated every 6 weeks using 3-methylhistidine tracer	24 weeks
Change in whole body fat volumes	Change in the amount of fat within the body, measured every 6 weeks using magnetic resonance imaging (MRI)	24 weeks
Change in liver fat volumes	Change in the amount of fat within the liver, measured every 6 weeks using magnetic resonance imaging (MRI)	24 weeks
Change in thigh muscle fat volumes	Change in the amount of fat within the vastus lateralis thigh muscle, measured every 6 weeks using magnetic resonance imaging (MRI)	24 weeks
Change in whole body muscle volumes	Change in the amount of muscle within the body, measured every 6 weeks using magnetic resonance imaging (MRI)	24 weeks
Change in muscle phosphocreatine synthesis rate	Change in the rate of phosphocreatine synthesis, measured every 6 weeks using magnetic resonance spectroscopy	24 weeks
Change in cerebral volume	Change in the volume of brain tissue, measured every 6 weeks using magnetic resonance imaging (MRI)	24 weeks
Change in cortical thickness	Change in the thickness of the brain cortex, measured every 6 weeks using magnetic resonance imaging (MRI)	24 weeks
Change in plasma metabolome	change in untargeted plasma metabolome profile measured every 6 weeks	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fasting blood lipid concentration	concentration of lipid within the blood	pre-intervention
Fasting blood lipid concentration	concentration of lipid within the blood	6 weeks
Fasting blood lipid concentration	concentration of lipid within the blood	12 weeks
Fasting blood lipid concentration	concentration of lipid within the blood	18 weeks
Fasting blood lipid concentration	concentration of lipid within the blood	24 weeks
liver function test: alanine transaminase (ALT)	concentration of ALT measured on blood sample	pre-intervention
liver function test: alanine transaminase (ALT)	concentration of ALT measured on blood sample	6 weeks
liver function test: alanine transaminase (ALT)	concentration of ALT measured on blood sample	12 weeks
liver function test: alanine transaminase (ALT)	concentration of ALT measured on blood sample	18 weeks
liver function test: alanine transaminase (ALT)	concentration of ALT measured on blood sample	24 weeks
liver function test: aspartate aminotransferase (AST)	concentration of AST measured on blood sample	pre-intervention
liver function test: aspartate aminotransferase (AST)	concentration of AST measured on blood sample	6 weeks
liver function test: aspartate aminotransferase (AST)	concentration of AST measured on blood sample	12 weeks
liver function test: aspartate aminotransferase (AST)	concentration of AST measured on blood sample	18 weeks
liver function test: aspartate aminotransferase (AST)	concentration of AST measured on blood sample	24 weeks
liver function test: Bilirubin	concentration of bilirubin measured on blood sample	pre-intervention
liver function test: Bilirubin	concentration of bilirubin measured on blood sample	6 weeks
liver function test: Bilirubin	concentration of bilirubin measured on blood sample	12 weeks
liver function test: Bilirubin	concentration of bilirubin measured on blood sample	18 weeks
liver function test: Bilirubin	concentration of bilirubin measured on blood sample	24 weeks
liver function test: Albumin	concentration of albumin measured on blood sample	pre-intervention
liver function test: Albumin	concentration of albumin measured on blood sample	6 weeks
liver function test: Albumin	concentration of albumin measured on blood sample	12 weeks
liver function test: Albumin	concentration of albumin measured on blood sample	18 weeks
liver function test: Albumin	concentration of albumin measured on blood sample	24 weeks
liver function test: Gamma glutamyl transferase (GGT)	concentration of GGT measured on blood sample	pre-intervention
liver function test: Gamma glutamyl transferase (GGT)	concentration of GGT measured on blood sample	6 weeks
liver function test: Gamma glutamyl transferase (GGT)	concentration of GGT measured on blood sample	12 weeks
liver function test: Gamma glutamyl transferase (GGT)	concentration of GGT measured on blood sample	18 weeks
liver function test: Gamma glutamyl transferase (GGT)	concentration of GGT measured on blood sample	24 weeks
Blood Haemoglobin concentration	haemoglobin concentration measured on a blood sample	pre intervention
Blood Haemoglobin concentration	haemoglobin concentration measured on a blood sample	6 weeks
Blood Haemoglobin concentration	haemoglobin concentration measured on a blood sample	12 weeks
Blood Haemoglobin concentration	haemoglobin concentration measured on a blood sample	18 weeks
Blood Haemoglobin concentration	haemoglobin concentration measured on a blood sample	24 weeks

Collaborators and Investigators

• Sponsor: University of Nottingham
• Collaborators: Biotechnology and Biological Sciences Research Council
• Investigators: Principal Investigator: Paul Greenhaff, PhD, University of Nottingham

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2024
• Primary Completion (Estimated): December 17, 2027
• Study Completion (Estimated): October 31, 2028

Study Registration Dates

• First Submitted: April 11, 2024
• First Submitted That Met QC Criteria: April 17, 2024
• First Posted (Actual): April 22, 2024

Study Record Updates

• Last Update Posted (Actual): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: overweight; Physical inactivity; Physical activity; lifestyle; middle-age
• Additional Relevant MeSH Terms: Mental Disorders; Glucose Metabolism Disorders; Metabolic Diseases; Nervous System Diseases; Neurologic Manifestations; Neurocognitive Disorders; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Insulin Resistance; Hyperinsulinism; Cognition Disorders; Muscular Atrophy; Atrophy; Metabolic Syndrome; Cognitive Dysfunction; Sarcopenia
• Other Study ID Numbers: BB/X015173/1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymised dataset will be made available to other researchers on request after study aims have been analysed and published. No patient identifiable data will be shared
• IPD Sharing Time Frame: Data will become available approximately 2 years after study completion and will be available for 20 years
• IPD Sharing Access Criteria: Although parts of the data set generated from this project will be available on open access platforms to support publications, access to the full data repository and tissue archive will be through requests made to the Management Board. Access will be subject to ethical constraints, the preservation of intellectual property (IP), and written acknowledgement that it is a research collaboration, with data ownership residing with the original research teams. Data will be shared subject to a data transfer agreement and confirmation that deletion of the shared data set will occur once analysis has been completed.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No