Prolonged period of muscle disuse circumstances such as limb immobilization and bedrest are associated with loss of skeletal muscle mass and function (Kandarian et al., 2006). This disuse-induced skeletal muscle atrophy has an important clinical implication to the elderly population because it is directly related to increased mortality and a decreased quality of life (Christensen et al., 1982). In the elderly population, age-dependent muscle loss is a serious health threat known as sarcopenia (Rosenberg, 1997). Thus, the elderly population is much vulnerable to the muscle disuse atrophy. Furthermore, age-related muscle loss leads to increased incidence of falls and fractures (Mithal et al., 2012). Epidemiological evidences report that hip fractures can lead to serious mobility impairment and thus have a strong correlation with mortality (Kim et al., 2012; Cornwall et al., 2004). Indeed, 34% of elderly hip fracture patients dying within 1 year of surgery and this possibility increases with age (Holt et al., 2012). Therefore, enhancing our understanding of the underlying mechanisms for skeletal muscle atrophy in elderly population is vital in order to develop prevention and therapeutic treatments to these problems. Mitochondrial dysfunction with advanced age plays an important role in sarcopenia due to its critical roles including ATP production, redox homeostasis as well as apoptosis (Handchin & Spiegelman, 2008). In the past decade, the peroxisome proliferator-activated receptor-ɤ coactivator-1α (PGC-1α) and sirtuins (SIRTs) emerged as key regulators for transcriptional and/or post-translational modifications, which are involved in mitochondrial biogenesis, dynamics, antioxidant defense system as well as mitophagy (Kim et al., 2017). PGC-1α activates mitochondrial biogenesis via coactivating nuclear-encoded mitochondrial protein transcription factors, and stimulates replication of mitochondrial DNA (mtDNA) (Lin et al., 2005). PGC-1α also has a regulatory mechanism for the expression of antioxidant enzymes such as SOD2, Catalase, and GPx1 (Wenz et al., 2009). In addition, recent studies have shown that PGC-1α is highly involved in mitochondrial fusion/fission and mitophagy machinery to maintain mitochondrial homeostasis, through interacting with mitochondrial fusion proteins (Mfn1/2 and Opa-1) and FoxO transcription factors (Sakellariou et al., 2016). SIRTs are NAD+-dependent protein deacetylases that, along with GCN5, plays a major role in controlling acetylation/deacetylation status of important intracellular proteins (Blander and Guarente, 2002). For example, deacetylation activity of SIRT1 is required for PGC-1α mediated mitochondrial biogenesis in skeletal muscles (Lagouge et al., 2006). Activity of NFkB and FoxO transcription factors, the key controllers for pro-inflammatory cytokine expression and mitophagy, are also regulated by SIRTs (Yeung et al 2004; Kawahara et al., 2009). SIRTs can also activates certain mitochondrial antioxidant enzymes (such as SOD2), enzymes in the TCA cycle and ETC via protein deacetylation resulting in enhancing mitochondrial oxidative phosphorylation (Lombard et al., 2007). Several experimental procedures have been utilized to boost PGC-1α and/or SIRTs activities to improve mitochondrial function and antioxidant capacity in various age-related diseases, such as neurodegenerative diseases, chronic inflammation, type 2 diabetes, and cardio vascular diseases (Rodgers et al., 2008; Wenz, 2011). Overexpression of PGC-1α and/or SIRTs is intended to ameliorate mitochondrial dysregulation and protein breakdown in aged skeletal muscles. Currently, however, direct evidences in the role of PGC-1α and SIRTs on aged muscles are limited. Therefore, this dissertation aims to investigate the impact of PGC-1α and SIRTs on skeletal muscle under two pathophysiological conditions, immobilization and aging. The work will focus on muscle mitochondrial quality control by investigating mitochondrial biogenesis, fusion and fission dynamics, mitophagy and oxidative capacity. The dissertation consists of three studies. The first study investigated the effect of muscle immobilization on mitochondrial fission/fusion and mitophagy in mice. The second study investigated the effect of PGC-1α overexpression on mitochondrial homeostasis in aged skeletal muscle in mice. The third study elucidated the impact of protein acetylation during aging in skeletal and cardiac muscles and the role of SIRTs and NAD+, the limiting factor of protein deacetylation.
University of Minnesota Ph.D. dissertation.June 2020. Major: Kinesiology. Advisors: Li Li Ji, Dawn Lowe. 1 computer file (PDF); viii, 85 pages.
Control of Mitochondrial Homeostasis In Disused and Aging Skeletal Muscle: Role of Pgc-1Alpha and Sirtuins.
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