Lysosomal Movement and Anabolic Resistance

Defining the Role of Lysosomal Movement in Age-associated Anabolic Resistance in Human Skeletal Muscle

Age-associated loss of muscle mass, termed sarcopenia, is strongly associated with functional impairment and physical disability in the elderly. Maintenance or growth of muscle mass is mainly driven by increased muscle protein synthesis (i.e. the generation of new muscle protein) in response to exercise and feeding. However, several investigations have shown that elderly individuals have a blunted protein synthetic response following protein intake. This inability of the elderly to properly respond to growth stimuli has been termed anabolic resistance and plays a significant role in the development of sarcopenia. However, the precise mechanisms underpinning anabolic resistance are unknown.

It is well established that muscle protein synthesis at the molecular level is regulated by a cellular protein complex called mTORC1. When exposed to a growth stimulus, mTORC1 has been shown to associate with lysosomes, i.e. the intracellular organelles responsible for the breakdown of cellular proteins, and subsequently moving towards the cell periphery.

This movement of lysosome-associated mTORC1 within the cell is believed to be vital for the activation of protein synthesis, as inhibition of lysosomal movement blunts mTORC1 activation in response to amino acids. Thus, dysregulation of lysosomal movement in ageing muscle may represent an underlying mechanism in the development of anabolic resistance. However, this area of research is unexplored in the context of human skeletal muscle. The investigators hypothesize that dysregulation of lysosomal movement plays a central role in the development of age-associated skeletal muscle anabolic resistance.

Study Overview

• Status: Unknown
• Conditions: Sarcopenia
• Intervention / Treatment: Dietary supplement: Essential amino acids

• Study Type: Interventional
• Enrollment (Anticipated): 26
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B152TT
      • Recruiting
      • School of Sport, Exercise and Rehabilitation Sciences at University of Birmingham
      • Contact: William Apro, Ph.D.; Phone Number: 0121 414 2875; Email: w.apro@bham.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

Be a non-smoking male within the specified age range for each group (young; 18-35 yrs, old; 65-75 yrs)

Have a BMI (body mass index, body weight/height in m2) between 18 and 25 kg/m2, which is considered a normal body mass index.

Be in good general health: no cardiovascular diseases or metabolic diseases.

Exclusion Criteria:

Health problems such as: heart disease , metabolic disease such as phenylketonuria, rheumatoid arthritis, uncontrolled hypertension, poor lung function, or any health condition that might put the participant at risk when participating in this study.

Generalized neuromuscular disease (such as Parkinson's disease or motorneuron disease).

Involvement in regular structured resistance exercise training at the time of the study.

Consumption of any analgesic drugs, anti-inflammatory drugs, or medication that is known to affect protein metabolism (beta-blockers, corticosteroids, NSAIDs).

Participants who have undergone muscle biopsy testing or isotope infusion procedures within the last 5 years.

Allergic to lidocaine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Resting leg of young males	Dietary supplement: Essential amino acids; 240 mg essential amino acids per kg body weight dissolved in 500 ml of water provided after exercise.
Experimental: Exercising leg of young males	Dietary supplement: Essential amino acids; 240 mg essential amino acids per kg body weight dissolved in 500 ml of water provided after exercise.
Experimental: Resting leg of elderly males	Dietary supplement: Essential amino acids; 240 mg essential amino acids per kg body weight dissolved in 500 ml of water provided after exercise.
Experimental: Exercising leg of elderly males	Dietary supplement: Essential amino acids; 240 mg essential amino acids per kg body weight dissolved in 500 ml of water provided after exercise.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lysosomal movement	Changes in intracellular localization of lysosomes will be measured via immunofluorescence	~360 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lysosomal movement in isolated muscle cells	Changes in intracellular localization of lysosomes will be measured via immunofluorescence	~30 minutes

Collaborators and Investigators

• Sponsor: University of Birmingham

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2017
• Primary Completion (Anticipated): August 30, 2018
• Study Completion (Anticipated): August 30, 2018

Study Registration Dates

• First Submitted: January 19, 2017
• First Submitted That Met QC Criteria: January 25, 2017
• First Posted (Estimate): January 26, 2017

Study Record Updates

• Last Update Posted (Actual): October 25, 2017
• Last Update Submitted That Met QC Criteria: October 24, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Muscular Atrophy; Atrophy; Sarcopenia
• Other Study ID Numbers: RG_16-200

Drug and device information, study documents

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