Older people are disproportionally affected by various chronic illnesses, typically related to frailty and metabolic syndrome. Both conditions cannot be cured but may be delayed by lifestyle changes. For instance, exercise increases muscle mass, enhances insulin sensitivity, and improves median survival. However, exercise is not always feasible for aged individuals. Hence, development of molecular approaches to mimic the health benefit of exercise can be especially important in order to delay age-related physical and metabolic dysfunction. The goal of this work is to test whether myostatin blockade can be viewed as such a useful exercise mimetic. We hypothesize that blocking myostatin, an endogenous inhibitor for muscle development, at late middle age will increase muscle mass and delay sarcopenia. While this hypothesis is supported by extensive previous studies with myostatin knockout and inhibitors in young animals, proof-of-concept within the context of aging is missing. This knowledge gap will be filled by the results from this work. In addition, based on our novel preliminary findings of interactions between myostatin and hepatocytes in cell culture, we propose a second hypothesis that liver can be a direct target of myostatin blockade. This explains the prior findings of improved liver function in myostatin knockout mice and our preliminary data showing decreased diet-induced hepatosteatosis in mice treated with myostatin inhibitory propeptide. Solid evidence to support this hypothesis, as will be collected in this work, will shift the paradigm of myostatin studies from exclusively muscle-focused to include liver and possibly other organs. This may bring novel opportunities for myostatin-based therapeutic developments to treat metabolic diseases. We will test our hypothesis using a wild-type mouse model beginning at late middle age, with myostatin blockade achieved by one-time injection of adeno-associated virus (AAV) encoding a myostatin-specific inhibitor, the propeptide mutant. Animals will be tested in parallel with standard low-fat and isocaloric high-fat diets, following two specific aims.
Aim -1 will focus on in vivo assessment of metabolic and functional performance at different points of aging, including measurement of respiration, insulin sensitivity, strength and endurance, as well as median and maximum lifespan.
Aim -2 will focus on muscle- and liver-specific signaling, mitochondrial activity, protein synthesis, and lipid metabolism.
The proposed research will determine if and how blocking myostatin, a muscle-secreted negative regulator for muscle development, will delay age-associated metabolic and functional decline. This work is directly relevant to the mission of NIH to pursue knowledge to extend healthy life and reduce burdens of illness and disability.
|Guo, Wen; Pencina, Karol M; O'Connell, Karyn et al. (2017) Administration of an activin receptor IIB ligand trap protects male juvenile rhesus macaques from simian immunodeficiency virus-associated bone loss. Bone 97:209-215|
|Guo, Wen; Miller, Andrew D; Pencina, Karol et al. (2016) Joint dysfunction and functional decline in middle age myostatin null mice. Bone 83:141-148|
|Wong, Siu; Kirkland, James L; Schwanz, Heidi A et al. (2014) Effects of thiol antioxidant ?-mercaptoethanol on diet-induced obese mice. Life Sci 107:32-41|
|Li, Michelle; Bhasin, Shalener; Bachman, Eric et al. (2014) A Combination of Fast-Clearance Nandrolone Plus Low-intensity Aerobic Exercise Improves RBC Indices in Anemic Aging Mice. J Hematol (Brossard) 3:22-24|
|Wong, Siu; Bhasin, Shalender; Serra, Carlo et al. (2013) Lopinavir/Ritonavir Impairs Physical Strength in Association with Reduced Igf1 Expression in Skeletal Muscle of Older Mice. J AIDS Clin Res 4:216|
|Guo, Wen; Wong, Siu; Bhasin, Shalender (2013) AAV-mediated administration of myostatin pro-peptide mutant in adult Ldlr null mice reduces diet-induced hepatosteatosis and arteriosclerosis. PLoS One 8:e71017|
|Guo, Wen; Bachman, Eric; Li, Michelle et al. (2013) Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells. Aging Cell 12:280-91|
|Guo, Wen; Wong, Siu; Li, Michelle et al. (2012) Testosterone plus low-intensity physical training in late life improves functional performance, skeletal muscle mitochondrial biogenesis, and mitochondrial quality control in male mice. PLoS One 7:e51180|
|Toraldo, Gianluca; Bhasin, Shalender; Bakhit, Mena et al. (2012) Topical androgen antagonism promotes cutaneous wound healing without systemic androgen deprivation by blocking ?-catenin nuclear translocation and cross-talk with TGF-? signaling in keratinocytes. Wound Repair Regen 20:61-73|
|Guo, Wen; Li, Yahui; Liang, Wentao et al. (2012) Beta-mecaptoethanol suppresses inflammation and induces adipogenic differentiation in 3T3-F442A murine preadipocytes. PLoS One 7:e40958|
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