Clinical trial NCT03326648: The Role of Muscle Protein Breakdown in the Regulation of Muscle Quality in Frail Elderly Individuals
Official title: The Role of Muscle Protein Breakdown in the Regulation of Muscle Quality in Frail Elderly Individuals
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Sarcopenia
Keywords: Sarcopenia
Frailty
Strength training
Autophagy
Lead sponsor: Norwegian School of Sport Sciences
Sponsor class: OTHER
Collaborators: name: University of Padova
name: University of Copenhagen
name: Tine
First posted: 2017-10-31
Enrollment: 34
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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

Primary outcomes:
measure: Single fiber specific force
timeFrame: Change from baseline at 10 weeks
Secondary outcomes:
measure: Lean mass
timeFrame: Change from baseline at 10 weeks
measure: Fat mass
timeFrame: Change from baseline at 10 weeks
measure: Bone mineral density
timeFrame: Change from baseline at 10 weeks
measure: Muscle strength of m. quadriceps
timeFrame: Change from baseline at 10 weeks
measure: Muscle size of m. quadriceps
timeFrame: Change from baseline at 10 weeks
measure: Fat infiltration of m. quadriceps
timeFrame: Change from baseline at 10 weeks
measure: Muscle activation
timeFrame: Change from baseline at 10 weeks
measure: Fractional Breakdown Rate
timeFrame: Measured over the last 14 days of the intervention period
measure: m. Vastus Lateralis thickness
timeFrame: Change from baseline at 10 weeks
measure: Chair stand performance
timeFrame: Change from baseline at 10 weeks
measure: Habitual gait velocity
timeFrame: Change from baseline at 10 weeks
measure: Maximal gait velocity
timeFrame: Change from baseline at 10 weeks
measure: Level/cellular location of Microtubule-associated protein 1A/1B-light chain 3 (LC3)
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: Level/cellular location of p62/Sequestosome-1
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: Level/cellular location of Lysosome-associated membrane glycoprotein 2 (LAMP2)
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: Level/cellular location of forkhead box O3 (FOXO3a)
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: Phosphorylation status and total level of ribosomal protein S6 kinase beta-1(P70S6K)
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: Phosphorylation status and total level of eukaryotic elongation factor 2 (eEF-2)
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: Phosphorylation status and total level of eukaryotic translation initiation factor 4E-binding protein 1 (4EBP-1)
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: Level/cellular location of muscle RING-finger protein-1 (Murf-1)
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: Level/cellular location of ubiquitin (Ub)
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: Blood serum glucose
timeFrame: Change from baseline at 10 weeks
measure: Blood serum insulin
timeFrame: Change from baseline at 10 weeks
measure: Blood plasma Hemoglobin A1c (HbA1c)
timeFrame: Change from baseline at 10 weeks
measure: Blood serum Triglycerides
timeFrame: Change from baseline at 10 weeks
measure: Blood serum High-density lipoproteins (HDL)
timeFrame: Change from baseline at 10 weeks
measure: Blood serum Low-density lipoproteins (LDL)
timeFrame: Change from baseline at 10 weeks
measure: Blood serum C-reactive protein (CRP)
timeFrame: Change from baseline at 10 weeks
measure: forkhead box protein O3 (FOXO3A) mRNA
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: forkhead box protein O1 (FOXO1) mRNA mRNA
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: hepatocyte growth factor (HGF) mRNA
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: insulin-like growth factor I (IGF1) mRNA
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: myostatin (MSTN) mRNA
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: E3 ubiquitin-protein ligase TRIM63 (TRIM63) mRNA
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: p62/Sequestosome-1 mRNA
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: muscle RING-finger protein-1 (Murf-1) protein 1 (4EBP-1) mRNA
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: Atrogin1 mRNA
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: Microtubule-associated protein 1A/1B-light chain 3 (LC3) mRNA
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: BCL2/adenovirus E1B interacting protein 3 (BNIP3) mRNA
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: PTEN-induced putative kinase 1 (PINK1) mRNA
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: TNF receptor associated factor 6 (TRAF6) mRNA
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: transcription factor EB (Tfeb) mRNA
timeFrame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
measure: Intramyocellular lipids
timeFrame: Change from baseline at 10 weeks
measure: Muscle fiber type distribution
timeFrame: Change from baseline at 10 weeks
measure: Muscle fiber cross-sectional area
timeFrame: Change from baseline at 10 weeks
measure: Muscle satellite cells
timeFrame: Change from baseline at 10 weeks
measure: Myonuclei
timeFrame: Change from baseline at 10 weeks
measure: Myonuclei number
timeFrame: Change from baseline at 10 weeks
measure: Myonuclei location
timeFrame: Change from baseline at 10 weeks
measure: Amount of mitochondria
timeFrame: Change from baseline at 10 weeks
measure: Location of mitochondria
timeFrame: Change from baseline at 10 weeks
Other outcomes:
Locations:
city: Oslo
country: Norway
facility: Norwegian School of Sport Sciences
Study officials:
affiliation: Norwegian School of Sport Sciences
name: Truls Raastad, Prof.
role: PRINCIPAL_INVESTIGATOR
References: