McGowan Institute for Regenerative Medicine faculty member Fabrisia Ambrosio, PhD, is an Associate Professor in the Department of Physical Medicine & Rehabilitation at the University of Pittsburgh. She holds secondary appointments in the Departments of Physical Therapy, Orthopaedic Surgery, and Microbiology & Molecular Genetics. In addition, she is a faculty member of the neurology residency program in the Department of Physical Therapy. Recently, Dr. Ambrosio and colleagues were awarded two NIH awards. Details on each follow:
Title: Dysfunctional muscle remodeling and regeneration in environmental disease (R01 from National Institute on Environmental Health Sciences)
Total funding: $2.6m
Investigators: Fabrisia Ambrosio (PI), Aaron Barchowsky (PI), William Wagner (co-I), Antonio D’Amore (co-I), Donna Stolz (co-I)
Project Description / Abstract: Arsenic is an odorless and tasteless semi-metal that contaminates drinking water supplies from natural deposits in the earth. It is estimated that almost 3.7 million individuals in the US, and over 140 million individuals worldwide, are exposed regularly to drinking water that exceed government arsenic standards. Increasing attention has been recently paid to the declines in functional mobility resulting from chronic arsenic exposure, which we now understand to pose a significant risk for causing skeletal muscle myopathies and atrophy, impairments that are among the greatest factors contributing to declines in functional mobility and strong predictors of mortality. However, many questions of the health impacts of environmental exposures throughout life remain, including the underlying mechanisms by which exposures negatively impact the cellular microenvironment, stem cell phenotype and, ultimately, tissue maintenance and healing capacity. The objective of this proposal is to elucidate mechanisms for arsenic-stimulated alteration of transcriptional circuitries that disrupt intra- and inter-cellular communication within the niche and compromise muscle structural integrity.
We propose two specific aims to test our central hypothesis that arsenic stimulates fibroblast-mediated pathogenic matrix alterations, resulting in stem cell dysfunction and, ultimately, impaired wound repair after injury. In Specific Aim 1, we will test the hypothesis that exposure to commonly encountered levels of arsenic in drinking water promotes pathologic matrix remodeling to impair muscle stem cell function and regenerative capacity. In Specific Aim 2, we will test the hypothesis that arsenic dysregulates fibroblast activation, driving an impaired muscle stem cell function and tissue repair response after injury. Success in these aims will both increase our understanding of the pathogenesis of arsenic-induced clinical symptoms of myasthenia, and will elucidate skeletal muscle microenvironmental factors controlling stem cell declines. The long-term goal is to create prevention and/or intervention strategies to improve health outcomes of individuals living in arsenic-endemic areas.
Title: The anti-aging effect of Klotho on skeletal muscle regeneration (R56 from National Institute on Aging)
Total funding: $177k
Investigators: Fabrisia Ambrosio (PI), Bennett Van Houten (PI), Aaron Barchowsky (co-I), Mauricio Rojas (co-I), Donna Stolz (co-I)
Project Description / Abstract: An age-related impairment of the regenerative capacity of aged muscle is a major contributor to declines in functional mobility and is associated with an increased morbidity in an elderly population. Following an acute injury, young skeletal muscle initiates a highly effective regenerative response, which largely restores the original architecture of the damaged fibers. Conversely, with increasing age, the regenerative response to injury results in a considerable scar tissue deposition at the expense of functional contractile tissue. Much of this healing defect has been attributed to an age-related decrease in muscle stem, or satellite, cell (MuSC) functionality. In response to skeletal muscle injury, MuSCs become activated from a quiescent state to repair damaged myofibers. However, it has been suggested that the increased fibrosis deposition following injury is a result of a myogenic-to-fibrogenic conversion of MuSCs. Fortunately, these age-related changes are reversible.
Elegant studies employing heterochronic parabiosis, in which the circulatory systems of young and aged animals are conjoined, have revealed that rejuvenation of the systemic microenvironment significantly restores both whole tissue and MuSC regenerative capacity in aged muscle. These findings implicate that circulating factors, such as the longevity protein Klotho, play a critical role in dictating skeletal muscle regenerative potential over time. Elucidation of the origin and nature of circulating factors contributing to the aged muscle phenotype is critical for the development of strategies to prevent, delay or reverse age-related declines. These studies will evaluate the role of circulating Klotho as a key anti-geronic protein contributing to the benefit of heterochronic parabiosis on aged muscle regeneration.
In Specific Aim 1, we will test the hypothesis that aged parabionts paired with young mice heterozygously deficient for Klotho will display significantly impaired skeletal muscle regeneration when compared to aged parabionts paired with young wild type mice. In Specific Aim 2, we will test the hypothesis that restoration of circulating Klotho to youthful levels reverse age-related declines in skeletal muscle regenerative capacity. We anticipate that success in these aims will have a long and lasting impact on the field as they will establish Klotho as an important anti-geronic factor that regulates MuSC activity essential for functional muscle regeneration after injury.
Congratulations Dr. Ambrosio!