Neuronal control of energy balance and modulation of muscle aging by the transcriptional coactivator PGC-1α

Cellular metabolic adaptations play a central role in the body's response to environmental changes and external stimuli and allow the maintenance of a proper energy balance. Transcriptional activators enable the integration of incoming signals and sensing of altered energy levels. Dysregulation of such metabolic pathways is a common mechanism of various tissue dysfunctions contributing to different diseases. A key player in cellular metabolism is the transcriptional coregulator Peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1α). PGC-1α is expressed in tissues with high basal oxidative capacity such as brain and muscle and regulates the expression of a plethora of genes in response to various external cues, including exercise and fasting. This makes PGC-1α an extremely powerful metabolic sensor and a potential therapeutic target in metabolic diseases. Similarly, its downregulation during muscle aging and its central function in the control of mitochondrial gene expression suggests its crucial role in the development of age-related muscle disorders. However, to establish the true therapeutic potential of PGC-1α, it is important to evaluate its impact on metabolic sensing in those tissues and the consequences of its modulation in such pathological conditions.
To determine the role of PGC-1α in central metabolic sensing and brain regulation of energy balance, we deleted the coactivator specifically in murine AgRP and POMC neurons located in the arcuate nucleus. The ablation of PGC-1α in POMC neurons did not reveal any major phenotype. Conversely, absence of PGC-1α in AgRP cells drove an increase in fat mass coupled with a reduction in locomotor activity and body temperature. Mice lacking the transcriptional coactivator in AgRP neurons exhibited a blunted leptin response and reduced food intake in fed and fasted conditions. Mechanistically, we demonstrated that fasting-induced AgRP expression is blunted in those mice and in an immortalized AgRP cell line, thereby leading to reduced feeding response upon fasting. Collectively, our results highlight a novel role for PGC-1α in neuronal regulation of energy homeostasis, which could be of therapeutic interest for the treatment of obesity and diabetes.
To determine the role of PGC-1α in muscle aging, we used muscle-specific PGC-1α deletion and overexpression mouse models. We confirmed that PGC-1α preserves mitochondrial function and protein expression, as well as muscle endurance during aging. More importantly, we identified a novel function for PGC-1α in muscle, involving the regulation of calcium homeostasis through the control of genes responsible for mitochondrial calcium uptake and mitochondrial association with the sarcoplasmic reticulum. We suspect that PGC-1α-mediated amelioration of calcium metabolism protected the old muscle against ER stress and prevented tubular aggregate formation, which all contributed to reducing muscle apoptosis. Finally, we used muscle cells treated with ceramide or thapsigargin to demonstrate that PGC-1α inhibited apoptosis initiated by mitochondrial or calcium homeostasis impairments. This strongly confirms the potential therapeutic usage of PGC-1α to reduce age-related muscle disorders but also other diseases involving calcium dysregulation.
In a final study, we used the same animal models that either received late-life endurance training or stayed untrained to determine the role of PGC-1α in exercise-mediated muscle improvements during aging. We demonstrated that PGC-1α could not only ameliorate muscle endurance but also age-associated motor dysfunctions. We also showed that PGC-1α muscle deletion led to pre-mature sarcopenia. Finally, we revealed that PGC-1α modulates many beneficial outcomes of exercise in the old muscle. PGC-1α muscle overexpression was sufficient to mimic or even override exercise beneficial effect on muscle aging. This further illustrates the importance of the coactivator in muscle aging and to maximize exercise positive outcomes in the old muscle.
In conclusion, the work undertaken in this thesis delineates new facets of PGC-1α-controlled metabolism. We described a role for PGC-1α as metabolic sensor in the brain and presented novel aspects of muscle metabolism regulated by the coactivator. We showed that it is protective in several ways against age-related muscle disorders and that it promotes exercise effects in this context. This work therefore improves our understanding of the biological processes regulated by PGC-1α and established the transcriptional regulator as a promising target for therapeutic approaches in metabolic and age-associated muscle diseases.