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Title:Preconditioned muscle-derived mesenchymal stem cells revitalize growth and function in aged skeletal muscle
Author(s):Huntsman, Heather
Director of Research:Boppart, Marni D.
Doctoral Committee Chair(s):Boppart, Marni D.
Doctoral Committee Member(s):Woods, Jeffrey A.; Rhodes, Justin S.; Dobrucki, Wawrzyniec
Department / Program:Kinesiology & Community Health
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Mesenchymal stem cell
Skeletal Muscle
α7 integrin
Abstract:Sarcopenia provides the underlying basis for loss of physical function and disability in older adults. In addition to sarcopenia’s direct effect on limiting mobility and movement, significant loss of muscle mass is associated the onset of type 2 diabetes, osteoporosis, obesity, and arthritis, as well as increased mortality. The prevalence of disability and co-morbidities in our growing aged population has the potential to add hundreds of billions of dollars to annual health care costs. In response to this impending health and financial burden, the scientific community has made a concerted effort to gain a better understanding of this condition with the goal of improved prevention and treatment strategies. The cause of age-related muscle loss is multifactorial and includes denervation, impairments in vascular function, and declining levels of circulating hormones and growth factors that repair tissue and promote growth. The complex etiology of sarcopenia warrants a multisystem approach in the development of therapeutic strategies to prevent and/or treat age-related disabilities. Our lab has defined a role for the α7β1 integrin, a transmembrane adhesion protein, in the protection of skeletal muscle from damage associated with mechanical force during exercise. Transgenic expression of the α7B integrin isoform in mouse muscle (α7Tg) additionally enhances new fiber formation, myofiber hypertrophy, and vessel growth following single or repeated bouts of eccentric exercise. One of the unique phenotypes of α7Tg mice is the accumulation of a stem cell population that we have isolated and characterized as a heterogeneous population of mesenchymal-like stem cells (MSCs). The ability for MSCs to significantly increase muscle and vessel growth post-exercise suggested that they provided the cellular basis for beneficial adaptations observed in α7Tg mice. Collectively, these studies demonstrated the potential for the α7 integrin and mMSCs in the prevention and/or treatment of age-related disabilities. The purpose of the first study was to develop a MSC-based therapy for the treatment of sarcopenia in mice. Preliminary experiments demonstrated that MSCs were dysfunctional in the aged microenvironment post-transplantation and did not effectively reverse age-related decrements in muscle mass and function. Thus, a preconditioning method was developed to promote survival and function in aged skeletal muscle post-transplantation. Our lab recently demonstrated that MSCs derived from skeletal muscle (mMSCs) are highly sensitive to mechanical strain and secrete numerous growth and neurotrophic factors that can impact MSC survival and local and distal tissue health. Thus, mMSCs isolated from young animals were mechanically strained and immediately injected into the hind limbs of 24 month old mice. In addition to measuring indices of muscle health, the impact of transplantation on distal tissues, including the brain, was also assessed. We hypothesized that mMSC paracrine factor release would allow for beneficial adaptations in both muscle and brain tissue. Transplantation stabilized the neuromuscular junction and increased muscle function, as well as increased neurogenesis in the hippocampus. Thus, these data suggest that mMSC preconditioning prior to transplantation may provide a novel method to prevent or reverse age-related impairments in muscle strength, neuroplasticity, and cognitive function. In a separate study we investigated the extent to which overexpression of the α7 integrin could preserve muscle mass and function with progression of age. α7Tg mice from our colonies were reserved for this purpose and muscle tissue was collected at 6mo, 16mo, and 24mo either in the sedentary state or following injury created by an acute bout of eccentric exercise. Skeletal muscles were analyzed for α7 integrin protein expression, markers of muscle damage, and mMSC quantitation. While α7 integrin protein declined in both α7Tg and wild type littermates, integrin expression was higher in α7Tg mice throughout the lifespan. The attrition rate was lower for α7Tg mice, perhaps due to improvements in maintenance of muscle mass, protection from sarcolemmal damage, and preservation of the mMSC response to injury. In conclusion, the studies presented in this dissertation provide evidence that both MSCs and the α7 integrin provide therapeutic targets for the prevention and treatment of age-related disabilities. Development of methods or approaches that can enhance α7 integrin protein or optimize endogenous MSC function in humans may provide a realistic and effective means increasing quality of life throughout the lifespan.
Issue Date:2014-05-30
Rights Information:Copyright 2014 Heather Huntsman
Date Available in IDEALS:2014-05-30
Date Deposited:2014-05

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