In healthy individuals, lean muscle accounts for 38 – 54% and 28 – 39% of total body mass in men and women respectively. These ranges are quite broad and are dependent upon multiple factors including age, physical activity level, overall health, and genetic makeup. In addition to its clear role in movement and locomotion, muscle is also a reservoir of glucose acting to buffer blood-glucose levels, a source of lactate and alanine for gluconeogenesis in the liver, as well as a major endocrine organ regulating the metabolic demands of adipose tissue, brain and bone. An ever increasing body of evidence links physical activity and the maintenance of lean muscle mass with a decreased risk of chronic disease as well as premature morbidity and mortality. A gradual loss of muscle mass with advancing age is physiologically normal. However, in a subset of individuals its increasingly rapid progression results in Sarcopenia, a major contributor to Frailty Syndrome. Effecting upwards of 5 million Americans per year, Cachexia is characterized by an excessive loss of muscle mass and increased mortality. It is now recognized as a complex metabolic condition associated with an underlying illness or chronic disease such as renal failure, cancer, rheumatoid arthritis, and AIDS.
The Neppl Research Group is focused on the molecular regulation of skeletal muscle homeostasis in health and disease. Our overarching goal is to understand how ncRNAs control the essential processes of myogenesis and hypertrophic growth, and how perturbations in these processes may lead to a disease state resulting in muscle atrophy. Using traditional biochemical and molecular biology techniques, in vivo and in vitro model systems, as well as next generation RNA sequencing, we seek to discover and understand the biological roles these ncRNAs play in the maintenance of lean muscle mass. Research activities in the laboratory fall within two main project areas:
lncRNA mediated regulation of skeletal muscle homeostasis and repair
Mechanistically, multiple cellular and molecular pathways regulating hypertrophic growth (anabolic pathways) and atrophy (catabolic pathways) are known. The major players regulating protein synthesis (i.e. Akt1, Igf1, mTor, SMADs 1/5/8, etc.) and protein degradation (i.e. Atrogin-1, MuRF1, MUSA, FOXO factors, etc.) have been well studied in the context of muscle hypertrophy and atrophy. Though much has been learned regarding the roles of these and other genes, we know relatively little about the roles of lncRNAs in physiological homeostasis of muscle and the progression of disease resulting in atrophy. Though still an emerging field, lncRNAs have been identified as critical regulators of essential cellular processes including cellular differentiation, fate determination, proliferation, and senescence. However, our knowledge of lncRNAs in skeletal muscle physiology is still in its infancy. The primary goal of this project is to understand the functions of lncRNAs in the maintenance of cellular and physiological homeostasis and in the etiology of muscle atrophy.
Regulation of the RNA Induced Silencing Complex is necessary for muscle homeostasis and physiological adaptations to stress
The RNA Induced Silencing Complex (RISC) is an evolutionarily conserved, multi-protein regulatory complex responsible for post-transcriptional gene regulation. Functionally, RISC inhibits translation of mRNA into protein through miRNA directed complementary binding to the 3’ untranslated region (UTR) of mRNA resulting loss of mRNA stability via removal of the 5’ m7G cap, deadenylation of the poly(A) tail, or through miRNA directed endonuclease activity. Given the biological necessity of miRNA/RISC, it is unclear how cells positively and negatively regulate its repressive (either endonuclease cleavage and/or mRNA destabilization) effects on mRNA translation to maintain physiological homeostasis. While much is known about the role of individual miRNAs in the regulation of muscle homeostasis and repair, the muscle specific signals and players regulating the activity of this essential muli-protein complex are relatively unknown. It is the overall goal of this project to understand signaling events that regulate the activity of miRNA/RISC under normal and pathological conditions.