Mitochondrial health is critical for skeletal muscle function and is improved by exercise training through both mitochondrial biogenesis and removal of damaged/dysfunctional mitochondria via mitophagy. The mechanisms underlying exercise-induced mitophagy have not been fully elucidated. Here, we show that acute treadmill running in mice causes mitochondrial oxidative stress at 3–12 h and mitophagy at 6 h post-exercise in skeletal muscle. These changes were monitored using a novel fluorescent reporter gene, pMitoTimer, that allows assessment of mitochondrial oxidative stress and mitophagy in vivo, and were preceded by increased phosphorylation of AMP activated protein kinase (Ampk) at tyrosine 172 and of unc-51 like autophagy activating kinase 1 (Ulk1) at serine 555. Using mice expressing dominant negative and constitutively active Ampk in skeletal muscle, we demonstrate that Ulk1 activation is dependent on Ampk. Furthermore, exercise-induced metabolic adaptation requires Ulk1. These findings provide direct evidence of exercise-induced mitophagy and demonstrate the importance of Ampk-Ulk1 signaling in skeletal muscle.

Lira VA, Benton CR, Yan Z, Bonen A. PGC-1␣ regulation by exercise training and its influences on muscle function and insulin sensitivity. Am J Physiol Endocrinol Metab 299: E145-E161, 2010. First published April 6, 2010; doi:10.1152/ajpendo.00755.2009.-The peroxisome proliferator-activated receptor-␥ (PPAR␥) coactivator-1␣ (PGC-1␣) is a major regulator of exercise-induced phenotypic adaptation and substrate utilization. We provide an overview of 1) the role of PGC-1␣ in exercise-mediated muscle adaptation and 2) the possible insulin-sensitizing role of PGC-1␣. To these ends, the following questions are addressed. 1) How is PGC-1␣ regulated, 2) what adaptations are indeed dependent on PGC-1␣ action, 3) is PGC-1␣ altered in insulin resistance, and 4) are PGC-1␣-knockout and -transgenic mice suitable models for examining therapeutic potential of this coactivator? In skeletal muscle, an orchestrated signaling network, including Ca 2ϩ -dependent pathways, reactive oxygen species (ROS), nitric oxide (NO), AMP-dependent protein kinase (AMPK), and p38 MAPK, is involved in the control of contractile protein expression, angiogenesis, mitochondrial biogenesis, and other adaptations. However, the p38␥ MAPK/PGC-1␣ regulatory axis has been confirmed to be required for exercise-induced angiogenesis and mitochondrial biogenesis but not for fiber type transformation. With respect to a potential insulinsensitizing role of PGC-1␣, human studies on type 2 diabetes suggest that PGC-1␣ and its target genes are only modestly downregulated (Յ34%). However, studies in PGC-1␣-knockout or PGC-1␣-transgenic mice have provided unexpected anomalies, which appear to suggest that PGC-1␣ does not have an insulin-sensitizing role. In contrast, a modest (ϳ25%) upregulation of PGC-1␣, within physiological limits, does improve mitochondrial biogenesis, fatty acid oxidation, and insulin sensitivity in healthy and insulin-resistant skeletal muscle. Taken altogether, there is substantial evidence that the p38␥ MAPK-PGC-1␣ regulatory axis is critical for exerciseinduced metabolic adaptations in skeletal muscle, and strategies that upregulate PGC-1␣, within physiological limits, have revealed its insulin-sensitizing effects. endurance exercise; angiogenesis; mitochondria; fatty acid metabolism; glucose SKELETAL MUSCLE IS HIGHLY ADAPTABLE to changes in contractile activity and to changes in the substrate/endocrine milieu. Although the molecular bases for these adaptive responses had remained uncertain for many years, the peroxisome proliferator-activated receptor-␥ (PPAR␥) coactivator 1␣ (PGC-1␣) has revealed itself to be a major regulator of exercise-induced phenotypic adaptation and substrate utilization. In the present paper, we provide an overview and perspective on the mechanisms by which PGC-1␣ is regulated by endurance exercise training as well as on the influence of PGC-1␣ on fiber type transformation, angiogenesis, mitochondrial biogenesis, lipid metabolism, and insulin sensitivity.The first part of this review examines 1) the pathways involved...

Skeletal muscle exhibits superb plasticity in response to changes in functional demands. Chronic increases of skeletal muscle contractile activity, such as endurance exercise, lead to a variety of physiological and biochemical adaptations in skeletal muscle, including mitochondrial biogenesis, angiogenesis, and fiber type transformation. These adaptive changes are the basis for the improvement of physical performance and other health benefits. This review focuses on recent findings in genetically engineered animal models designed to elucidate the mechanisms and functions of various signal transduction pathways and gene expression programs in exercise-induced skeletal muscle adaptations.