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The Role of Muscle Protein Breakdown in the Regulation of Muscle Quality in Frail Elderly Individuals

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ClinicalTrials.gov Identifier: NCT03326648
Recruitment Status : Completed
First Posted : October 31, 2017
Last Update Posted : April 11, 2018
Sponsor:
Collaborators:
University of Padova
University of Copenhagen
Tine
Information provided by (Responsible Party):
Truls Raastad, Norwegian School of Sport Sciences

Brief Summary:
The purpose of this study is to investigate mechanisms underlying the reduction in muscle quality (the ratio between muscle strength and muscle size) with aging, and to investigate how these factors are affected by strength training and protein supplementation. It is already established that muscle quality defined as the ratio between the strength and the size of a muscle is improved with strength training, even in frail elderly individuals. However, the relative contribution of factors such as activation level, fat infiltration, muscle architecture and single fiber function is unknown. The main focus of this study is to investigate the relationship between muscle quality and muscle protein breakdown, as insufficient degradation of proteins is hypothesized to negatively affect muscle quality.

Condition or disease Intervention/treatment Phase
Sarcopenia Other: Strength training Dietary Supplement: Protein supplementation Not Applicable

Detailed Description:

Aging is associated with impaired skeletal muscle function. This is evident not only by a reduced capacity to generate force and power at the whole muscle level, but also by a decline in individual muscle fiber contraction velocity and force generation. Combined with muscle atrophy, these changes lead to reduced muscle strength and quality and loss off physical function with age. Clinically, muscle quality may be a better indicator of overall functional capacity than absolute muscle strength. Thus, identifying the mechanisms underlying the age-related loss of muscle quality is of high relevance for the prevention of functional impairment with aging. The explanation for the loss of muscle quality with aging seems to be multifactorial, with alterations in voluntary muscle activation, muscle architecture, fat infiltration and impaired contractile properties of single muscle fibers being likely contributors. Single fiber specific force seems to be related to myosin heavy chain (MHC) content, which is thought to reflect the number of available cross-bridges. The reduction of single fiber specific force with aging may thus be a consequence of reduced synthesis of MHC and/or increased concentration of non-contractile tissue (e.g. intramyocellular lipids).

Some studies in mice also indicate attenuated activity in some of the pathways responsible for degradation of muscle proteins with aging (especially autophagy). As a result, damaged proteins and organelles are not removed as effectively as they should, which could ultimately compromise the muscle's ability to produce force. In addition, reduced efficiency of mitophagy and lipophagy (two specific forms of autophagy), may indirectly affect single fiber specific force, through oxidative damage by reactive oxygen species (ROS) and increased levels of intramyocellular lipids, respectively. Although animal studies indicate attenuated autophagic function, exercise seems to restore the activity in this pathway. Whether this also is the case in humans is unknown. Thus, the purpose of this study is to investigate how the different factors contributing to reduced muscle quality in frail elderly individuals, with emphasis on the relationship between muscle quality and autophagy, may be counteracted by a specific strength training program targeting muscle quality and muscle mass.

In this randomized controlled trial the investigators will aim to recruit frail elderly individuals, as muscle quality is shown to be low in this population. As a consequence, the potential for improved muscle quality is expected to be large. Subjects will be randomized to two groups; one group performing strength training twice a week for 10 weeks in addition to receiving daily protein supplementation. The other group will only receive the protein supplement. Several tests will be performed before and after the intervention period, including a test day where a biopsy is obtained both at rest, and 2.5 hours following strength training + protein supplementation or protein supplementation only. This will provide information about the regulation of muscle protein breakdown in a resting state, following protein intake and following strength training in combination with protein intake. As this will be done both before and after the training period, it will also provide information on how long-term strength training affects the activity in these systems.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking Description: Subjects and testers will not be blinded. All analyses of muscle samples will be performed blinded.
Primary Purpose: Basic Science
Official Title: The Role of Muscle Protein Breakdown in the Regulation of Muscle Quality in Frail Elderly Individuals
Actual Study Start Date : September 1, 2016
Actual Primary Completion Date : December 20, 2017
Actual Study Completion Date : March 1, 2018

Arm Intervention/treatment
Experimental: Strength training + protein supplement
Two sessions of strength training each week in addition to daily protein supplementation for 10 weeks.
Other: Strength training
Heavy load strength training performed twice a week for 10 weeks.
Other Name: Resistance training

Dietary Supplement: Protein supplementation
Dietary protein supplement (protein-enriched milk with 0,2 % fat). 0,33 l each day for 10 weeks.

Experimental: Protein supplement
Daily protein supplementation for 10 weeks.
Dietary Supplement: Protein supplementation
Dietary protein supplement (protein-enriched milk with 0,2 % fat). 0,33 l each day for 10 weeks.




Primary Outcome Measures :
  1. Single fiber specific force [ Time Frame: Change from baseline at 10 weeks ]
    A measure of muscle quality at the single fiber level. Biopsies obtained from m. Vastus Lateralis


Secondary Outcome Measures :
  1. Lean mass [ Time Frame: Change from baseline at 10 weeks ]
    Measured by a Dual-energy X-ray absorptiometry (DXA) scan

  2. Fat mass [ Time Frame: Change from baseline at 10 weeks ]
    Measured by a Dual-energy X-ray absorptiometry (DXA) scan

  3. Bone mineral density [ Time Frame: Change from baseline at 10 weeks ]
    Measured by a Dual-energy X-ray absorptiometry (DXA) scan

  4. Muscle strength of m. quadriceps [ Time Frame: Change from baseline at 10 weeks ]
    Maximal isometric and dynamic muscle strength of m. quadriceps

  5. Muscle size of m. quadriceps [ Time Frame: Change from baseline at 10 weeks ]
    Cross-sectional area of m. quadriceps measured by a Computed Tomography scan

  6. Fat infiltration of m. quadriceps [ Time Frame: Change from baseline at 10 weeks ]
    Fat infiltration of m. quadriceps measured by a Computed Tomography scan

  7. Muscle activation [ Time Frame: Change from baseline at 10 weeks ]
    Voluntary activation level during a maximal isometric knee extension using the interpolated twitch technique

  8. Fractional Breakdown Rate [ Time Frame: Measured over the last 14 days of the intervention period ]
    Measurement of fractional breakdown rate by the use of orally provided Deuterium Oxide, biopsies and blood samples

  9. m. Vastus Lateralis thickness [ Time Frame: Change from baseline at 10 weeks ]
    Measured by ultrasound

  10. Chair stand performance [ Time Frame: Change from baseline at 10 weeks ]
    Time (sec) to stand up from a chair five times

  11. Habitual gait velocity [ Time Frame: Change from baseline at 10 weeks ]
    Time (sec) to walk 6 meters at habitual gait velocity

  12. Maximal gait velocity [ Time Frame: Change from baseline at 10 weeks ]
    Time (sec) to walk 6 meters as fast as possible

  13. Level/cellular location of Microtubule-associated protein 1A/1B-light chain 3 (LC3) [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  14. Level/cellular location of p62/Sequestosome-1 [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  15. Level/cellular location of Lysosome-associated membrane glycoprotein 2 (LAMP2) [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  16. Level/cellular location of forkhead box O3 (FOXO3a) [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  17. Phosphorylation status and total level of ribosomal protein S6 kinase beta-1(P70S6K) [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  18. Phosphorylation status and total level of eukaryotic elongation factor 2 (eEF-2) [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  19. Phosphorylation status and total level of eukaryotic translation initiation factor 4E-binding protein 1 (4EBP-1) [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  20. Level/cellular location of muscle RING-finger protein-1 (Murf-1) [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  21. Level/cellular location of ubiquitin (Ub) [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  22. Blood serum glucose [ Time Frame: Change from baseline at 10 weeks ]
    Fasted

  23. Blood serum insulin [ Time Frame: Change from baseline at 10 weeks ]
    Fasted

  24. Blood plasma Hemoglobin A1c (HbA1c) [ Time Frame: Change from baseline at 10 weeks ]
    Fasted

  25. Blood serum Triglycerides [ Time Frame: Change from baseline at 10 weeks ]
    Fasted

  26. Blood serum High-density lipoproteins (HDL) [ Time Frame: Change from baseline at 10 weeks ]
    Fasted

  27. Blood serum Low-density lipoproteins (LDL) [ Time Frame: Change from baseline at 10 weeks ]
    Fasted

  28. Blood serum C-reactive protein (CRP) [ Time Frame: Change from baseline at 10 weeks ]
    Fasted

  29. forkhead box protein O3 (FOXO3A) mRNA [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  30. forkhead box protein O1 (FOXO1) mRNA mRNA [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  31. hepatocyte growth factor (HGF) mRNA [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  32. insulin-like growth factor I (IGF1) mRNA [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  33. myostatin (MSTN) mRNA [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  34. E3 ubiquitin-protein ligase TRIM63 (TRIM63) mRNA [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  35. p62/Sequestosome-1 mRNA [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  36. muscle RING-finger protein-1 (Murf-1) protein 1 (4EBP-1) mRNA [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  37. Atrogin1 mRNA [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  38. Microtubule-associated protein 1A/1B-light chain 3 (LC3) mRNA [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  39. BCL2/adenovirus E1B interacting protein 3 (BNIP3) mRNA [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  40. PTEN-induced putative kinase 1 (PINK1) mRNA [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  41. TNF receptor associated factor 6 (TRAF6) mRNA [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  42. transcription factor EB (Tfeb) mRNA [ Time Frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks ]
    Biopsies from m. Vastus Lateralis analyzed by western blot

  43. Intramyocellular lipids [ Time Frame: Change from baseline at 10 weeks ]
    Oil-Red-O staining of muscle sections. Biopsy from m. Vastus Lateralis analyzed by immunohistochemistry

  44. Muscle fiber type distribution [ Time Frame: Change from baseline at 10 weeks ]
    Biopsy from m. Vastus Lateralis analyzed by immunohistochemistry

  45. Muscle fiber cross-sectional area [ Time Frame: Change from baseline at 10 weeks ]
    Biopsy from m. Vastus Lateralis analyzed by immunohistochemistry

  46. Muscle satellite cells [ Time Frame: Change from baseline at 10 weeks ]
    Biopsy from m. Vastus Lateralis analyzed by immunohistochemistry

  47. Myonuclei [ Time Frame: Change from baseline at 10 weeks ]
    Biopsy from m. Vastus Lateralis analyzed by immunohistochemistry

  48. Myonuclei number [ Time Frame: Change from baseline at 10 weeks ]
    Biopsy from m. Vastus Lateralis analyzed by confocal microscopy

  49. Myonuclei location [ Time Frame: Change from baseline at 10 weeks ]
    Biopsy from m. Vastus Lateralis analyzed by confocal microscopy

  50. Amount of mitochondria [ Time Frame: Change from baseline at 10 weeks ]
    Biopsy from m. Vastus Lateralis analyzed by confocal microscopy

  51. Location of mitochondria [ Time Frame: Change from baseline at 10 weeks ]
    Biopsy from m. Vastus Lateralis analyzed by confocal microscopy



Information from the National Library of Medicine

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Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age > 65
  • Frail or pre-frail according to the Fried Frailty Criteria or Short Physical Performance Battery (SPPB) score <6.
  • Mini Mental State Examination score > 18

Exclusion Criteria:

  • Diseases or injuries contraindicating participation
  • Lactose intolerance
  • Allergy to milk
  • Allergy towards local anesthetics (xylocain)
  • Use of anticoagulants that cannot be discontinued prior to the muscle biopsy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03326648


Locations
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Norway
Norwegian School of Sport Sciences
Oslo, Norway, 0863
Sponsors and Collaborators
Truls Raastad
University of Padova
University of Copenhagen
Tine
Investigators
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Principal Investigator: Truls Raastad, Prof. Norwegian School of Sport Sciences

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Responsible Party: Truls Raastad, Prof., Norwegian School of Sport Sciences
ClinicalTrials.gov Identifier: NCT03326648     History of Changes
Other Study ID Numbers: STAS
First Posted: October 31, 2017    Key Record Dates
Last Update Posted: April 11, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Truls Raastad, Norwegian School of Sport Sciences:
Sarcopenia
Frailty
Strength training
Autophagy
Additional relevant MeSH terms:
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Sarcopenia
Muscular Atrophy
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Atrophy
Pathological Conditions, Anatomical
Signs and Symptoms