A consequence of aging is the progressive loss of skeletal muscle mass, termed sarcopenia, leading to functional decline and impaired quality of life. One method to counteract sarcopenia is progressive resistance exercise training (PRT), which increases muscle mass and strength. The effectiveness of PRT is unparalleled by other treatments, but there is considerable inter-individual heterogeneity in responsiveness (defined by degree of muscle hypertrophy). We hypothesize a major cause of blunted muscle regrowth among low responders is an exaggerated response to inflammatory mediators consequent to abnormally high muscle expression of cytokine receptors (IL-6R, TNFR1, TWEAK-R (aka Fn14)), which we have termed muscle inflammation susceptibility (MuIS). We recently completed a four-arm, randomized clinical trial to determine the optimal PRT dosage for older adults (~65y) which identified 2 high intensity sessions, separated by a low intensity session (HLH) maximizes muscle regrowth (NCT02442479). Even in this optimized prescription, there are low responders. Therefore, in an ongoing follow-up randomized, double-blind, placebo-controlled clinical trial (NCT02308228) enrolling 100 atrophied older adults (65+ y), we are combining HLH with an anti-inflammatory drug (metformin) in an attempt to overcome the low responder phenotype. PRT-induced muscle hypertrophy requires net muscle protein synthesis (MPS), which in turn requires a sufficient pool of active ribosomes for the translation of new proteins. The accumulation of ribosomes (i.e. ribosome biogenesis) appears to be central to net MPS and PRT- induced muscle hypertrophy. We have shown load-induced ribosome biogenesis likely regulates the magnitude of muscle hypertrophy during PRT and that inhibiting ribosome biogenesis in vitro prevents myotube hypertrophy. The proposed experiments will test the central hypothesis that MuIS is responsible for blunted muscle hypertrophy by limiting ribosome biogenesis during PRT, via three aims:
Aim 1 : To determine if MuIS status influences PRT-induced muscle regrowth in older adults. Approach: Leveraging our ongoing PRT clinical trial, participants will be clustered by K-means cluster analysis as MuIS(+) or MuIS(-) based on muscle cytokine receptor expression. The primary outcome will be change in type II myofiber size after PRT. We will also determine if blunted muscle ribosome biogenesis occurs in MuIS(+) subjects.
Aim 2 : To determine if inflammation directly inhibits ribosome biogenesis and myotube hypertrophy. Approach: Primary satellite cells isolated from muscle biopsies of these subjects will be differentiated to myotubes and exposed to growth stimulation in the presence and absence of a pro-inflammatory milieu.
Aim 3 : To determine if metformin shifts MuIS(+) to MuIS(-). Approach: MuIS status will be determined in muscle biopsies collected over the course of treatment at three time points. These experiments are expected to significantly impact the field by increasing our understanding of MuIS and its bearing on the propensity for skeletal muscle regrowth in atrophied older adults.
Progressive resistance training is the most effective intervention identified to combat sarcopenia; however, the response to exercise is blunted and highly variable in some of this population. Prospective identification of individuals, based on cytokine receptors, and determining the effectiveness of metformin in improving the muscle inflammation phenotype, may contribute to the development of a low cost, personalized approach to prevent frailty in the elderly. Furthermore, by uncovering novel mechanisms of blunted muscle growth such as ribosomal biogenesis, we can create more precise and targeted therapies to increase quality of life in aging atrophied adults.
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| Bamman, Marcas M; Roberts, Brandon M; Adams, Gregory R (2018) Molecular Regulation of Exercise-Induced Muscle Fiber Hypertrophy. Cold Spring Harb Perspect Med 8: |
| Stec, Michael J; Thalacker-Mercer, Anna; Mayhew, David L et al. (2017) Randomized, four-arm, dose-response clinical trial to optimize resistance exercise training for older adults with age-related muscle atrophy. Exp Gerontol 99:98-109 |
