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

Brief Summary

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.

Primary Outcomes

Secondary Outcomes

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