PGC-1α Improves Glucose Homeostasis in Skeletal Muscle in an Activity-Dependent Manner

Abstract

Metabolic disorders are a major burden for public health systems globally. Regular exercise improves metabolic health. Pharmacological targeting of exercise mediators might facilitate physical activity or amplify the effects of exercise. The peroxisome proliferator–activated receptor γ coactivator 1α (PGC-1α) largely mediates musculoskeletal adaptations to exercise, including lipid refueling, and thus constitutes such a putative target. Paradoxically, forced expression of PGC-1α in muscle promotes diet-induced insulin resistance in sedentary animals. We show that elevated PGC-1α in combination with exercise preferentially improves glucose homeostasis, increases Krebs cycle activity, and reduces the levels of acylcarnitines and sphingosine. Moreover, patterns of lipid partitioning are altered in favor of enhanced insulin sensitivity in response to combined PGC-1α and exercise. Our findings reveal how physical activity improves glucose homeostasis. Furthermore, our data suggest that the combination of elevated muscle PGC-1α and exercise constitutes a promising approach for the treatment of metabolic disorders.

Transcriptional Network Analysis in Muscle Reveals AP-1 as a Partner of PGC-1α in the Regulation of the Hypoxic Gene Program

“…In an extension of these studies, we now, however, found additional genes involved in this process that show an additional, or in the case of Nr0b2, even an exclusive synergistic activation by exercise in the PGC-1␣ transgenic animals. Thus, combined with previous descriptions of muscle plasticity in these mice postexercise in regard to insulin sensitivity (29), our present findings reiterate the importance of bona fide exercise even in a genetic model for endurance training such as the PGC-1␣ musclespecific transgenic animals. In summary, our data provide a first insight into the transcriptional network controlled by PGC-1␣ in muscle cells.…”

“…The running protocol is as follows: 10 m/min for 5 min with an increase of 2 m/min every 5 min until 26 m/min and an inclination of 5 degrees. The speed of 26 m/min was kept until exhaustion of the mice (7,28,29). Mice were killed and tissues were collected 3 h after exercise.…”

Distinct populations of adipogenic and myogenic Myf5-lineage progenitors in white adipose tissues

“…It has been well established that slow myofi bers are more resistant to damage under stress conditions, such as muscular dystrophy and diabetes (43)(44)(45). In addition, slow myofi bers express high levels of the mitochondrial biogenesis-determinant genes Pgc1 ␣ and PPAR ␦ ; therefore, they are more sensitive to insulin-regulated glucose uptake and may provide beneficial metabolic effects (46)(47)(48)(49). Expression of CD34 or Sca1, two stem-cell markers, is associated with the myogenic potential of progenitor cells derived from bone marrow, blood, and embryonic vasculature (50)(51)(52)(53).…”

Loss ofPgc-1αexpression in aging mouse muscle potentiates glucose intolerance and systemic inflammation

“…PGC-1␣ is considered a master regulator of mitochondrial biogenesis and function, acting as an upstream regulatory switch for gene pathways controlling oxidative phosphorylation, fatty acid oxidation, reactive oxygen species detoxification, and mitochondrial density. Overexpression of PGC-1␣ in muscle protects aging mice from age-related muscle wasting and glucose intolerance (50,52), and yet tight regulation of PGC-1␣ expression is required to maintain efficient glucose and lipid handling in obese mice (6,19,51). Expression of Pgc-1␣ in muscle is low in type 2 diabetics and related family members (2,21,33,38) but can be increased with exercise to possibly prevent or reverse metabolic abnormalities (3,25,44,49).…”