Age-related muscle weakness is a significant problem that carries enormous healthcare costs resulting from its contributions to disability, impaired mobility & independence and even overall mortality. Mounting evidence indicates that this weakness results more from a loss of muscle quality (strength per unit muscle mass) than muscle atrophy, indicating a need to pursue interventional strategies other than increasing muscle mass. Recent, limited, data suggest that trimetazidine (TMZ) , a non-hemodynamic anti-angina drug, may enhance muscle function in aged rats, without affecting muscle size. However those data include only behavioral performance tests, with no direct measures of muscle strength; neither do they discriminate among muscular or neural mechanisms. This proposed work addresses these gaps by providing definitive measures of muscle contractile function following treatment with TMZ. Our laboratory has published findings that aged muscles that exhibit impaired muscle quality, also show impaired Ca2+ release by the sarcoplasmic reticulum (SR) ? the intramuscular storehouse of calcium that is mobilized to produce muscle contraction. Further evidence indicates that TMZ may act to address several mechanism linked to muscle quality and SR function, including: reduced autophagy, increased oxidative injury and altered lipid metabolism. Thus, there is a theoretical basis for TMZ to improve aged muscle function, supported by our preliminary data, by increasing aged muscle contractility, reducing SR lipid peroxidation and enhancing SR Ca2+ release. Combined with our published data, these findings provide the basis for this small, self-contained pre-clinical study. Our central hypothesis is that TMZ treatment will enhance force production by improving SR function in aged muscles. We further predict that TMZ will stimulate aged muscle autophagy, and reduce SR lipid peroxidation. Accordingly, our proposed study will combine a range of methodologies to assess the effects of TMZ on muscle function and morphology. We will test contractile responses to both neural (in situ) and direct (ex vivo) electrical stimulation in an established rat model of aging. This combination will allow us to determine the relative contribution of neuromuscular vs. intramuscular mechanisms changes in muscle force. We will also directly assess SR function (e.g., Ca2+ release) lipid peroxidation and morphology (via electron microscopy). We will also assess effect of TMZ on basal autophagic flux in skeletal muscle. While we predict that TMZ will improve aged muscle function by improving SR function, our approach will allow us to probe alternative mechanisms (e.g., neuromuscular junction stability, muscle hypertrophy), should the results warrant. If our hypotheses are confirmed, short-term future work will be directed at more thoroughly investigating mechanisms of action (e.g., lipidomic analysis of the SR) as well as dose-response characteristics will be pursued. The long-term goals will be directed to identifying interventions targeted to improve or maintain muscle quality in older adults. In the long term, this could include, but not be limited to, a re-purposing of TMZ as a geriatric intervention.
It is traditionally thought that muscle size must be increased to increase strength, but increasing evidence indicates that age-related weakness exceeds reduction in muscle size. It is therefore important to identify strategies other than increasing muscle size for improving strength in the elderly, as age-related weakness contributes to disability, morbidity and mortality. This proposal is for a small, self-contained, pre-clinical study to determine off-label use of trimetazidine, an established cardiac medication, can positively affect the magnitude and mechanisms of muscle weakness in aged rodents.
