Mechanisms of Disuse Atrophy in Human Skeletal Muscle (iMOB)

Muscular Atrophy Clinical Trial

— iMOB  

Official title:

Harnessing Muscle-specific Atrophy Susceptibility to Disentangle the Mechanisms of Disuse Atrophy in Human Skeletal Muscle Atrophy (iMOB)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04199923
• Other study ID #: 1031809
• Status: Recruiting
• Phase: N/A
• Start date: April 1, 2019
• Est. completion date: September 1, 2021

Study information

• Verified date: August 2020
• Source: University of Nottingham
• Contact: Edward JO Hardy, MBBCh
• Phone: 07890429460
• Email: edward.hardy2[@]nottingham.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Loss of muscle can be caused by a variety of stimuli and results in reduced mobility and strength and also impacts whole body health. Whilst it is known that muscles waste the process by which this occurs is not well understood. Furthermore, whilst some muscles waste quickly others seem resistant to the effects of disuse.

This study aims to evaluate how quickly changes in muscles start to occur, and investigate the processes which underlie muscle atrophy. By studying muscles which waste quickly and those which are resistant to atrophy this study aims to identify the different processes which lead to muscle loss. This study will also evaluate the differences in muscle changes between young and old people.

Description:

Skeletal muscles host ~40% of all protein in the body. Muscles are not only crucial for locomotion but also represent the body's largest metabolically active tissue, glucose disposal site and fuel reservoir for other organs in pathological conditions (i.e., supply of amino acids to the liver for gluconeogenesis). Muscle atrophy is characterized by a reduction in cross sectional area (CSA) and length and occurs in many common illnesses (e.g. cancers (1), renal/heart failure, sepsis, genetic diseases, neurodegenerative disorders etc). It is also prevalent in situations of reduced neural input such as leg casting after fractures (2), bed-rest, spinal cord injury (3), space flight and chronic physical inactivity. Atrophy results in a loss of muscle power and strength (which is related to increased morbidity and mortality (4)) and reduced capacities for whole-body glucose storage and metabolism which causes insulin resistance. Strategies to oppose atrophy are limited but include mechanical loading (5) and the synergistic anabolic effects of nutrients. Although muscle atrophy is of great clinical importance, relatively little mechanistic research has been done in humans. Thus, the aim of this study is to assess the link between the variation in muscle physiological responses to disuse atrophy with variation in protein turnover and molecular-networks. This will not only provide new hypotheses for physiological regulation of human muscle and generate 'intervention targets' derived from clinically relevant human studies, it will also improve understanding of whether the response to disuse is altered with age and determine if mechanistic differences in atrophy resistant and atrophy sensitive muscles might explain inter-muscular variation in susceptibility to atrophy.

This study aims to define the molecular and metabolic mechanisms causing disuse atrophy in both young and older individuals and explore how and why some muscles are protected against it. The study will also assess temporal aspects of disuse atrophy (in younger individuals only) to explore the mechanistic basis for the more rapid atrophy observed in the early days of disuse.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: September 1, 2021
• Est. primary completion date: May 1, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Group 1 and 2: Male, Age 18-40, BMI 18-35

• Group 3: Male, Age 65-80, BMI 18-35

Exclusion Criteria:

• BMI > 35 / <18

• Female

• Personal or Family History of Venous Thromboembolism

• Significant medical comorbidities

Related Conditions & MeSH terms

• Atrophy
• Immobility Syndrome
• Muscular Atrophy
• Muscular Disorders, Atrophic

Intervention

Behavioral:
• Single leg immobilisation
Immobilisation with single leg suspension immobilisation

Locations

Country	Name	City	State
United Kingdom	Graduate Entry Medical School	Derby	Derbyshire

Sponsors (2)

Lead Sponsor	Collaborator
University of Nottingham	Biotechnology and Biological Sciences Research Council

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in muscle volume (cm3)	MRI assessment of muscle volume in Tibialis Anterior (TA) and Medial Gastrocnemius (MG) in immobilised vs non-immobilised leg, pre and post immobilisation	14 days in group 1. 5 days in groups 2 and 3
Primary	Changes in muscle thickness (cm)	Ultrasound scan (USS) assessment of muscle thickness in Tibialis Anterior (TA) and Medial Gastrocnemius (MG) in immobilised vs non-immobilised leg, pre and post immobilisation	14 days in group 1. 5 days in groups 2 and 3
Primary	Changes in muscle cross surface area (cm2)	Ultrasound assessment of muscle cross surface area, in tibialis anterior (TA) and Medial Gastrocnemius (MG) in immobilised vs non-immobilised pre and post immobilisation	14 days in group 1. 5 days in groups 2 and 3
Primary	Changes in muscle fibre length (cm)	Ultrasound assessment of muscle fibre length in tibialis anterior (TA) and Medial Gastrocnemius (MG) in immobilised vs non-immobilised pre and post immobilisation	14 days in group 1. 5 days in groups 2 and 3
Primary	Changes in muscle fibre pennation angle (degrees)	Ultrasound assessment of muscle fibre pennation angle in tibialis anterior (TA) and Medial Gastrocnemius (MG) in immobilised vs non-immobilised pre and post immobilisation	14 days in group 1. 5 days in groups 2 and 3
Primary	Muscle Protein Synthesis (MPS) rate (%/hr)	IV tracer (Individual muscle MPS in TA+MG muscles in immobilised vs non immobilised legs)	Over 8 hours following immobilisation period
Primary	Muscle Protein Breakdown (MPB) rate (%/hr)	IV Pulse tracers (IV tracers to give muscle specific MPB measures of TA+MG muscles in immobilised vs non-immobilised legs)	Over 8 hours following immobilisation period
Secondary	Muscle blood flow	contrast enhanced ultrasound (CEUS) assessment of muscle blood flow in immobilised vs non-immobilised legs (TA+MG muscle specific)	over 5 minutes (following immobilisation period)
Secondary	Leg blood flow	Doppler assessment of leg blood flow through common femoral artery in fed and fasted states in both immobilised and non-immobilised leg	Over 5 minutes (following immobilisation period)
Secondary	Anabolic Signalling	Measurement of anabolic signalling pathways by western blot (comparison between immobilised vs non immobilised TA + MG muscles)	14 days in group 1. 5 days in groups 2 and 3
Secondary	Catabolic Signaling	Measurement of proteasome and lysosomal and related catabolic signalling pathways by western blot (comparison between immobilised vs non immobilised TA + MG muscles)	14 days in group 1. 5 days in groups 2 and 3
Secondary	RNA sequencing	complete RNA sequencing of immobilised vs non immobilised TA + MG muscles to determine gene set enrichment and pathway analysis	14 days in group 1. 5 days in groups 2 and 3
Secondary	Histology	Morphological assessment of muscle fibres by histological techniques (comparing immobilised vs non immobilised TA + MG muscles)	14 days in group 1. 5 days in groups 2 and 3
Secondary	Mitochondrial respiration	Measurement of mitochondrial respiration to assess different complex activity in immobilised vs non-immobilised TA + MG muscles	14 days in group 1. 5 days in groups 2 and 3
Secondary	Intramuscular electromyography (iEMG)	Electrically induced maximum force development and fatigability in TA + MG muscles pre and post immobilisation	14 days in group 1. 5 days in groups 2 and 3
Secondary	Muscle power	Assessment of changes in muscle power secondary to immobilisation through 1 rep max (kg) pre and post immobilisation	14 days in group 1. 5 days in groups 2 and 3
Secondary	Cardio pulmonary fitness	Cardiopulmonary Exercise Testing (CPET) to assess changes in aerobic fitness (V02 max, anaerobic threshold and Watt Max) following immobilisation	14 days in group 1. 5 days in groups 2 and 3