The Impact of Bed Rest, Aging and NMES on Skeletal Muscle

The Impact of Bed Rest and Aging on Muscle Mass and Muscle Function: Effects of Neuromuscular Electrical Stimulation

Loss of muscle mass is common phenotypic trait of muscular disuse and ageing. The loss of muscle mass affects, among others, the ability to maintain homeostasis of glucose metabolism and the energy reservoir in catabolic conditions, while also affecting mechanical muscle function which can cause detrimental impairments in general functional status and hence quality of life.

However, a limited amount of research has attempted to elucidate molecular regulators of muscle mass loss following bed rest in older individuals and across genders. Consequently, the mechanistic drivers are unresolved and there are currently no effective therapeutic strategies to counteract muscle wasting and loss of function in individuals submitted to bed rest e.g. during hospitalization.

Purpose The purpose is to examine the effects of 5 days of bed rest on muscle mass, including myofibrillar protein synthesis and breakdown, and muscle function, and elucidate molecular regulators of muscle mass loss and metabolic pathways, while also investigating if potential negative effects can be counteracted by daily NeuroMuscular Electrical Stimulation (NMES) across different age and genders.

Methods The study is designed as a randomized controlled cross-over 5-day bed rest study including a group of healthy young (18-30 years) and healthy old (65-80 years) men and women.

Participants will receive daily electrical stimulation (NMES) of the thigh muscles (30 min x 3/day) on one leg (ES), while the other leg serves as a control (CON).

Participants will be tested at baseline (pre) and after (post) intervention for muscle strength, muscle power, balance, and muscle activation. Blood samples are collected at several time points and muscle biopsies are sampled pre- and post-intervention along with assessment of whole-body muscle mass and thigh muscle mass.

Scientific exposition The results from the study can potentially provide insight into the adaptive mechanisms associated with NMES training and muscular disuse on both cellular- and whole-body level. The understanding of the underlying mechanisms is crucial for the application of NMES in a therapeutic context and will furthermore help us understand the basic mechanism regulating the skeletal muscle mass during both training and muscular disuse.

Overall, the results can potentially help establishing treatments to counteract loss of muscle mass, muscle function and muscle health during periods of muscular disuse.

Study Overview

• Status: Recruiting
• Conditions: Muscle Function; Neuromuscular Electrical Stimulation; Disuse Atrophy (Muscle) of Lower Extremities; Myofibrillar Protein Synthesis
• Intervention / Treatment: Other: Bed rest; Other: Neuromuscular electrical stimulation

• Study Type: Interventional
• Enrollment (Anticipated): 32
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sofie K Hansen; Phone Number: 0045 22423877; Email: sofie.krarup.hansen.01@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2400
    • Recruiting
    • Bispebjerg Hospital
    • Contact: Sofie K Hansen, Mac; Phone Number: 0045 22423877; Email: sofie.krarup.hansen.01@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy
• Age between 18-30 or 65-80 years
• Injury free in the lower extremities (No previous or current knee injuries or knee pain)
• Normal weight
• Consumes normal diet

Exclusion Criteria:

• Cognitive impairment affecting the ability to participate in the study.
• Health related contraindications to participating in the intervention (i.e., bed rest and/or NMES), such as eczema and rash on the lower extremities
• Smoker
• Obesity
• Not able to speak or understand Danish.
• Acute or chronic diseases such as diabetes, cancer, embolism, infection, cardio-vascular diseases
• Use of medication which affects myofibrillar protein synthesis or the skeletal muscle tissue
• Use of other medication (e.g. anticoagulants, adrenal cortex hormone [within the last 3 months] etc.)
• Previous or current use of anabolic steroids
• Previous participation in research trials involving deuterium oxide or another stable isotope tracer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Bed rest- Control; One leg will be subjected to disuse by bed rest and will not receive further treatment during the bed rest period.	Other: Bed rest; 5 days of strict bed rest
Experimental: Bed rest + NMES; One leg will be subjected to disuse by bed rest and will in addition receive neuromuscular electrical stimulation of the quadriceps muscle 3 times/day.	Other: Bed rest; 5 days of strict bed rest; Other: Neuromuscular electrical stimulation; Unilateral neuromuscular electrical stimulation (m. Quadriceps)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Myofiber cross-sectional area	Histochemical analysis of type I and type II myofiber cross-sectional area	Change from baseline after bed rest intervention
Assessment of myofibrillar protein synthesis	Quantification of myofibrillar protein synthesis using the stable-isotope amino acid tracer deuterium oxide (D2O)	Assessed during the period from pre-intervention biopsies (day 0, first day of bed rest) to post-intervention biopsies (day 5, last day and cessation of bed rest)
Change in maximal isometric muscle strength and superimposed twitch	Maximal isometric voluntary quadriceps strength combined with the superimposed twitch technique to assess maximal strength and voluntary muscle activation	Change from baseline after bed rest intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in total Akt protein assessed by Western blot	Assessment of Akt protein by Western Blot analysis using muscle tissue from vastus lateralis	Change from baseline after bed rest intervention
Change in total mTOR protein assessed by Western blot	Assessment of mTOR protein by Western Blot analysis using muscle tissue from vastus lateralis	Change from baseline after bed rest intervention
Change in total MuRF-1 protein assessed by Western blot	Assessment of MuRF-1 protein by Western Blot analysis using muscle tissue from vastus lateralis	Change from baseline after bed rest intervention
Change in total Atrogin-1 protein assessed by Western blot	Assessment of Atrogin-1 protein by Western Blot analysis using muscle tissue from vastus lateralis	Change from baseline after bed rest intervention
Change in total myostatin protein assessed by Western blot	Assessment of myostatin protein by Western Blot analysis using muscle tissue from vastus lateralis	Change from baseline after bed rest intervention
Change in quadriceps muscle morphology and architecture by ultrasound scan	Ultrasound scan of rectus femoris and vastus lateralis muscle thickness and of vastus lateralis pennation angle	Change from baseline after bed rest intervention
Change in body composition by DEXA scan	Assessment of whole body and regional lean mass and fat	Change from baseline after bed rest intervention
Change in leg extensor power	Muscle power of the lower extremities assessed using the Nottingham power rig	Change from baseline after bed rest intervention
Change in sway - postural balance	Measurement of displacement of center of pressure during unilateral and bilateral stance	Change from baseline after bed rest intervention
Change in triglycerides	Fasting blood samples are collected for analysis of triglycerides	Day 0, day 2, day 4 and day 5
Change in cholesterol	Fasting blood samples are collected for later analysis of cholesterol	Day 0, day 2, day 4 and day 5
Change in C-reactive protein (CRP)	Fasting blood samples are collected for analysis of CRP values	Day 0, day 2, day 4 and day 5

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Accelerometer data	Collecting accelerometer data to quantify habitual activities prior to bed rest period	3 days prior to the intervention
Accelerometer data	Collecting accelerometer data to monitor activity throughout the intervention	Throughout the 5 day intervention

Collaborators and Investigators

• Sponsor: Bispebjerg Hospital
• Investigators: Principal Investigator: Charlotte Suetta, Professor, Bispebjerg Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2022
• Primary Completion (Anticipated): February 28, 2023
• Study Completion (Anticipated): August 1, 2024

Study Registration Dates

• First Submitted: August 22, 2022
• First Submitted That Met QC Criteria: November 14, 2022
• First Posted (Actual): November 15, 2022

Study Record Updates

• Last Update Posted (Actual): November 15, 2022
• Last Update Submitted That Met QC Criteria: November 14, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic
• Other Study ID Numbers: H-20038614

Drug and device information, study documents

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