An interventional study of Strength training and Protein supplementation in Sarcopenia, sponsored by Truls Raastad. Completed at 1 site in Norway. Open to participants aged 65 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2018-04-11.
Sponsored by Truls Raastad · Not applicable, Interventional, and Basic science
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.
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.
Exclusion Criteria:
Two sessions of strength training each week in addition to daily protein supplementation for 10 weeks.
Other: Strength training · Dietary Supplement: Protein supplementation
Daily protein supplementation for 10 weeks.
Dietary Supplement: Protein supplementation
Heavy load strength training performed twice a week for 10 weeks.
Also known as: Resistance training
Dietary protein supplement (protein-enriched milk with 0,2 % fat). 0,33 l each day for 10 weeks.
Single fiber specific force
A measure of muscle quality at the single fiber level. Biopsies obtained from m. Vastus Lateralis
Time frame: Change from baseline at 10 weeks
Lean mass
Measured by a Dual-energy X-ray absorptiometry (DXA) scan
Time frame: Change from baseline at 10 weeks
Fat mass
Measured by a Dual-energy X-ray absorptiometry (DXA) scan
Time frame: Change from baseline at 10 weeks
Bone mineral density
Measured by a Dual-energy X-ray absorptiometry (DXA) scan
Time frame: Change from baseline at 10 weeks
Muscle strength of m. quadriceps
Maximal isometric and dynamic muscle strength of m. quadriceps
Time frame: Change from baseline at 10 weeks
Muscle size of m. quadriceps
Cross-sectional area of m. quadriceps measured by a Computed Tomography scan
Time frame: Change from baseline at 10 weeks
Fat infiltration of m. quadriceps
Fat infiltration of m. quadriceps measured by a Computed Tomography scan
Time frame: Change from baseline at 10 weeks
Muscle activation
Voluntary activation level during a maximal isometric knee extension using the interpolated twitch technique
Time frame: Change from baseline at 10 weeks
Fractional Breakdown Rate
Measurement of fractional breakdown rate by the use of orally provided Deuterium Oxide, biopsies and blood samples
Time frame: Measured over the last 14 days of the intervention period
m. Vastus Lateralis thickness
Measured by ultrasound
Time frame: Change from baseline at 10 weeks
Chair stand performance
Time (sec) to stand up from a chair five times
Time frame: Change from baseline at 10 weeks
Habitual gait velocity
Time (sec) to walk 6 meters at habitual gait velocity
Time frame: Change from baseline at 10 weeks
Maximal gait velocity
Time (sec) to walk 6 meters as fast as possible
Time frame: Change from baseline at 10 weeks
Level/cellular location of Microtubule-associated protein 1A/1B-light chain 3 (LC3)
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
Level/cellular location of p62/Sequestosome-1
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
Level/cellular location of Lysosome-associated membrane glycoprotein 2 (LAMP2)
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
Level/cellular location of forkhead box O3 (FOXO3a)
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
Phosphorylation status and total level of ribosomal protein S6 kinase beta-1(P70S6K)
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
Phosphorylation status and total level of eukaryotic elongation factor 2 (eEF-2)
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
Phosphorylation status and total level of eukaryotic translation initiation factor 4E-binding protein 1 (4EBP-1)
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
Level/cellular location of muscle RING-finger protein-1 (Murf-1)
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
Level/cellular location of ubiquitin (Ub)
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
Blood serum glucose
Fasted
Time frame: Change from baseline at 10 weeks
Blood serum insulin
Fasted
Time frame: Change from baseline at 10 weeks
Blood plasma Hemoglobin A1c (HbA1c)
Fasted
Time frame: Change from baseline at 10 weeks
Blood serum Triglycerides
Fasted
Time frame: Change from baseline at 10 weeks
Blood serum High-density lipoproteins (HDL)
Fasted
Time frame: Change from baseline at 10 weeks
Blood serum Low-density lipoproteins (LDL)
Fasted
Time frame: Change from baseline at 10 weeks
Blood serum C-reactive protein (CRP)
Fasted
Time frame: Change from baseline at 10 weeks
forkhead box protein O3 (FOXO3A) mRNA
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
forkhead box protein O1 (FOXO1) mRNA mRNA
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
hepatocyte growth factor (HGF) mRNA
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
insulin-like growth factor I (IGF1) mRNA
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
myostatin (MSTN) mRNA
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
E3 ubiquitin-protein ligase TRIM63 (TRIM63) mRNA
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
p62/Sequestosome-1 mRNA
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
muscle RING-finger protein-1 (Murf-1) protein 1 (4EBP-1) mRNA
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
Atrogin1 mRNA
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
Microtubule-associated protein 1A/1B-light chain 3 (LC3) mRNA
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
BCL2/adenovirus E1B interacting protein 3 (BNIP3) mRNA
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
PTEN-induced putative kinase 1 (PINK1) mRNA
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
TNF receptor associated factor 6 (TRAF6) mRNA
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
transcription factor EB (Tfeb) mRNA
Biopsies from m. Vastus Lateralis analyzed by western blot
Time frame: Before and 2.5 hours after acute training session both at baseline and after 10 weeks
Intramyocellular lipids
Oil-Red-O staining of muscle sections. Biopsy from m. Vastus Lateralis analyzed by immunohistochemistry
Time frame: Change from baseline at 10 weeks
Muscle fiber type distribution
Biopsy from m. Vastus Lateralis analyzed by immunohistochemistry
Time frame: Change from baseline at 10 weeks
Muscle fiber cross-sectional area
Biopsy from m. Vastus Lateralis analyzed by immunohistochemistry
Time frame: Change from baseline at 10 weeks
Muscle satellite cells
Biopsy from m. Vastus Lateralis analyzed by immunohistochemistry
Time frame: Change from baseline at 10 weeks
Myonuclei
Biopsy from m. Vastus Lateralis analyzed by immunohistochemistry
Time frame: Change from baseline at 10 weeks
Myonuclei number
Biopsy from m. Vastus Lateralis analyzed by confocal microscopy
Time frame: Change from baseline at 10 weeks
Myonuclei location
Biopsy from m. Vastus Lateralis analyzed by confocal microscopy
Time frame: Change from baseline at 10 weeks
Amount of mitochondria
Biopsy from m. Vastus Lateralis analyzed by confocal microscopy
Time frame: Change from baseline at 10 weeks
Location of mitochondria
Biopsy from m. Vastus Lateralis analyzed by confocal microscopy
Time frame: Change from baseline at 10 weeks
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