Clinical trial NCT04199923: Mechanisms of Disuse Atrophy in Human Skeletal Muscle (iMOB)
Official title: Harnessing Muscle-specific Atrophy Susceptibility to Disentangle the Mechanisms of Disuse Atrophy in Human Skeletal Muscle Atrophy (iMOB)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Muscular Atrophy
Immobility Syndrome
Lead sponsor: University of Nottingham
Sponsor class: OTHER
Collaborators: name: Biotechnology and Biological Sciences Research Council
First posted: 2019-12-16
Enrollment: 36
Sex: MALE
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: unilateral limb immobilisation study
Primary purpose: BASIC_SCIENCE

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Changes in muscle volume (cm3)
timeFrame: 14 days in group 1. 5 days in groups 2 and 3
measure: Changes in muscle thickness (cm)
timeFrame: 14 days in group 1. 5 days in groups 2 and 3
measure: Changes in muscle cross surface area (cm2)
timeFrame: 14 days in group 1. 5 days in groups 2 and 3
measure: Changes in muscle fibre length (cm)
timeFrame: 14 days in group 1. 5 days in groups 2 and 3
measure: Changes in muscle fibre pennation angle (degrees)
timeFrame: 14 days in group 1. 5 days in groups 2 and 3
measure: Muscle Protein Synthesis (MPS) rate (%/hr)
timeFrame: Over 8 hours following immobilisation period
measure: Muscle Protein Breakdown (MPB) rate (%/hr)
timeFrame: Over 8 hours following immobilisation period
Secondary outcomes:
measure: Muscle blood flow
timeFrame: over 5 minutes (following immobilisation period)
measure: Leg blood flow
timeFrame: Over 5 minutes (following immobilisation period)
measure: Anabolic Signalling
timeFrame: 14 days in group 1. 5 days in groups 2 and 3
measure: Catabolic Signaling
timeFrame: 14 days in group 1. 5 days in groups 2 and 3
measure: RNA sequencing
timeFrame: 14 days in group 1. 5 days in groups 2 and 3
measure: Histology
timeFrame: 14 days in group 1. 5 days in groups 2 and 3
measure: Mitochondrial respiration
timeFrame: 14 days in group 1. 5 days in groups 2 and 3
measure: Intramuscular electromyography (iEMG)
timeFrame: 14 days in group 1. 5 days in groups 2 and 3
measure: Muscle power
timeFrame: 14 days in group 1. 5 days in groups 2 and 3
measure: Cardio pulmonary fitness
timeFrame: 14 days in group 1. 5 days in groups 2 and 3
Other outcomes:
Locations:
city: Derby
country: United Kingdom
facility: Graduate Entry Medical School
state: Derbyshire
Study officials:
affiliation: University of Nottingham
name: Bethan E Phillips, PhD
role: PRINCIPAL_INVESTIGATOR
References: