Accelerated Sarcopenia
Testing a mitochondrial targeted intervention in a genetic model of accelerated sarcopenia
Sarcopenia, or age-related of loss of muscle mass and function, is associated with a decline in quality of life for elderly populations and few effective treatment options. Superoxide dismutase 1 (SOD1) knockout mice show an accelerated sarcopenia phenotype due to elevated oxidative stress in the absence of SOD1. We are using this established model of oxidative stress induced sarcopenia to test the mechanisms by which the mitochondrial targeted peptide reverses age-related skeletal muscle dysfunction. We are administering SS-31 to SOD1 knockout mice in this model to assess the effects of this treatment on skeletal muscle and mitochondrial structure-function. This project combines both non-invasive in vivo assays of function, with histological and biochemical analyses to determine skeletal muscle fiber type, metabolite and protein concentrations, and muscle fiber respiration and oxidant production. The effect of SS-31 on muscle function, mitochondrial quality, and redox homeostasis has exciting potential as a translational therapeutic treatment for human sarcopenia.
Diet and Aging
Aging increases susceptibility to nutrition stress by sugar in skeletal and cardiac muscle
Cardiac and skeletal muscle function decline with age and are further affected by poor nutrition. The growing prevalence of processed foods has significantly increased our risk to over consume refined sugars. While sugar has been linked to the development of type 2 diabetes and obesity, less is known as to how it can affect aging skeletal and cardiac muscle. We have found that skeletal muscle function of old mice can benefit from high fat low sugar diet, but less so from high fat high sugar diet. We also have found that low fat high sugar diet can accelerate cardiac hypertrophy in old mice. Improving mitochondrial bioenergetics through treatment with SS-31 is able to protect against nutritional stress, however, the mechanisms are still unclear. By using mitochondrial therapeutics as well as proteomic analysis, in vivo and ex vivo mitochondrial function assays, we will be able to determine how aging mitochondria responds to nutrition stress and accelerates the age-related decline in cardiac and skeletal muscle function.
Mito Targeted Interventions
SS-31 improves mitochondrial function and skeletal muscle performance in aged mice
Acute doses of the mitochondrial targeted peptide elamipretide (SS-31) are capable of rapidly improving mitochondrial bioenergetics and muscle function. SS-31 is known to bind directly to cardiolipin on the inner mitochondrial membrane. 8 weeks of SS-31 treatment in mice decreases mono-lyso cardiolipin, an isoform of cardiolipin that is a precursor to mature cardiolipin as well as a product of oxidative damage. SS-31 improved bioenergetics, resistance to fatigue, and overall improved redox state (figure). Additionally, 8-week treatment with SS-31 shows a very robust decrease in protein S-glutathionylation in aged mice indicating that decreased redox stress contributes to improved mitochondrial and overall muscle function. See figure below under “Proteome and post-translational modifications altered by age.” (Campbell et al., 2018)
Mitochondrial respiration in bluefin tuna red muscle and heart
Bluefin tuna have advanced physiological mechanisms to maintain performance as they travel through varying temperature zones in the ocean. One of these adaptations is the ability to maintain red muscle at a high temperature relative to surrounding ocean water especially during particularly deep dives where temperatures can reach below 10 degrees Celsius. This makes mitochondria of tuna red muscle of particular interest as it is continually operating at temperatures in a very fixed range. The temperature of the heart meanwhile is necessarily maintained at that of the surrounding water and must therefore operate under a much larger range of temperatures. By performing mitochondrial preparations from both heart and red muscle we can evaluate how the unique thermal biology of this high-performance pelagic fish has shaped the temperature dependence of mitochondrial energetics in these two tissues. (manuscript in preparation)
Proteome and post-translational modifications altered by age
Mitochondrial changes are often cited as a key driver in the pathological effects of aging, especially in high metabolic demand tissues like the skeletal muscle. However, recent work makes it clear that the role of mitochondria in aging is much more complicated that simply a mismatch in ATP supply and demand. We have been focusing on the intersection of mitochondrial function, redox biology, energetics and post-translational modifications to explore the mechanisms by which mitochondria alter both tissue function and the adaptive responses to stress in aging tissues. With our collaborators in the Villen, MacCoss, and Qian labs we are using mitochondrial targeted manipulations to examine the mechanisms by which changes in specific aspects of mitochondrial function affect the redox and phosphor-proteomes in aged muscle to alter both cell function and adaptive responses to stress.
SS-31 as a preventative intervention for sarcopenia caused by oxidative stress
Superoxide dismutase (SOD) is the primary enzyme responsible for converting superoxide to hydrogen peroxide and molecular oxygen. Mice lacking SOD have accelerated aging of the neuromuscular junction and skeletal muscle that is at least partially due to increased oxidative stress. By treating animals with the mitochondrial targeted peptide SS-31 we hope to improve mitochondrial function and skeletal muscle performance by intervening before increased redox stress and accumulation of oxidative damage causes performance decline and loss of muscle mass. We can also time the intervention of SS-31 to precede the known performance and function decline in skeletal muscle of SOD mice to evaluate the potential of SS-31 as a prevention of sarcopenia, the age-related loss of muscle mass and function. (work is ongoing)