BADERC- Laurie J. Goodyear

Laurie J. Goodyear, Ph.D.

Exercise Regulation of Glucose Transport in Skeletal Muscle

It is well established that the performance of regular physical exercise results in numerous health benefits, including a reduced risk of developing type 2 diabetes. Physical exercise is also widely accepted as a clinically important modality to decrease blood glucose concentrations in patients with diabetes, due largely to an increase in the rate of glucose transport into the contracting skeletal muscles and an increase in insulin sensitivity in the period following exercise. Despite the profound clinical importance of the metabolic effects of exercise, until recently, there was little focus on understanding the underlying molecular mechanisms that mediate these responses. A major goal of the work in the Goodyear laboratory is to elucidate the mechanisms through which physical exercise increases glucose transport and insulin sensitivity in skeletal muscle.

Work from the Goodyear laboratory has shown that muscle contractile activity increases glucose transport in muscle through intracellular signal transduction mechanisms that are distinct from that of insulin. The putative signals have long been elusive, but in recent years they have identified the AMP-activated protein kinase (AMPK) as a mediator of insulin-independent glucose transport in skeletal muscle. These studies had a major impact on biological research and contributed to worldwide interest in AMPK as a master regulator of metabolic and transcriptional functions in tissues and cells throughout the body, as well as identifying AMPK as a novel drug target for the treatment of diabetes. The lab’s work in the AMPK field is currently focused on elucidating downstream substrates for AMPK regulation of glucose transport and insulin sensitivity in skeletal muscle. To this end, the Goodyear laboratory has been at the forefront of studies investigating the rab GAP protein Akt substrate of 160 kDa (AS160), as well as TBC1D1, the AS160 paralog that is almost exclusively expressed in skeletal muscle. Their work also investigates the role of the AMPK kinase LKB1 in glucose and fatty acid metabolism, insulin signaling, and post-exercise insulin signaling in both skeletal muscle and heart.

Studies from the Goodyear lab focused on defining contraction signals have revealed that AMPK is not the exclusive mediator of contraction-stimulated glucose transport. Therefore, an important focus of the lab is to elucidate the additional signaling systems that mediate insulin-independent glucose transport. Recently, work from the laboratory has led to the exciting discovery that the sucrose non-fermenting AMPK-related kinase (SNARK) is a novel, insulin-independent signal that mediates glucose uptake in skeletal muscle. In addition, they have evidence that SNARK and additional AMPK-related kinases may be important for many of the additional metabolic effects of exercise, and are currently working toward investigating the function of these proteins in skeletal muscle. These molecules are likely to draw considerable attention in the diabetes field in the near future.

In addition to the acute effects of a single bout of exercise on muscle glucose metabolism, exercise training can lead to numerous chronic adaptations to skeletal muscle. These adaptations are fundamental for the salutary effects of increased physical activity on several human diseases including diabetes and congestive heart failure. The stimulus for these changes is thought to be initiated by each individual bout of exercise, as a single exercise session can significantly alter rates of gene transcription and protein synthesis. In working to understand how the contraction stimulus signals the transcriptional and protein synthetic processes, the Goodyear laboratory has discovered that exercise robustly alters the activity of numerous protein kinases including ERK, c-jun kinase, p38 kinase, Akt, GSK-3, and AMPK. In addition, they find that several novel proteins are robustly up regulated by exercise training, including SNARK and tribbles 3 (TRB3). Studies are underway to determine if the effects of chronic exercise to cause skeletal muscle remodeling involves the activation of these intracellular signal transduction pathways.

To address all of these questions the laboratory uses a combination of molecular and physiological approaches including contraction of rodent skeletal muscles in vitro and in situ, knockout and transgenic mice, and a highly successful technique to overexpress foreign proteins into adult rodent skeletal muscle using electroporation. In conjunction with the Proteomics Core laboratory at Joslin, the Goodyear laboratory has developed methods to identify phosphorylation sites of endogenous skeletal proteins muscle using mass spectrometry. Furthermore, they have recently developed a novel imaging technique that can monitor the effects of muscle contraction on the localization and movement of fluorescently labeled proteins in the muscle fibers of live, anesthetized mice. These discoveries, made largely using animal models, have provided the basis for additional work on human subjects by the Goodyear lab and other groups around the world. All of these investigations should help define the molecular basis for the important adaptations that occur in skeletal muscle in response to exercise, and will have important ramifications for patients with metabolic and cardiovascular diseases.

References:

Kramer HF, Witczak CA, Fujii N, Hirshman MF, Jessen N, Taylor EB, Arnolds D, Sakamoto K, Goodyear LJ. Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle. Diabetes. 2006; 55(7): 2067-76
Kramer HF, Witczak CA, Taylor EB, Fuji N, Hirshman MF, Goodyear LJ. AS160 regulates insulin-and contraction-stimulated glucose uptake in mouse skeletal muscle. J Biol Chem. 2006; 281: 31478-31485
Witczak CA, Fujii N, Hirshman MF, Goodyear LJ. Ca2+/calmodulin-dependent protein kinase kinase-alpha regulates skeletal muscle glucose uptake independent of AMP-activated protein kinase and Akt activation. Diabetes. 2007; 56(5): 1403-9
Rockl KS, Hirshman MF, Brandauer J, Fujii N, Witters LA, Goodyear LJ. Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift. Diabetes. 2007; 56(8): 2062-9
Kramer HF, Fujii N, Witczak CA, Hirshman MF, Goodyear LJ. The calmodulin-binding domain of AS160 regulates contraction- but not insulin-stimulated glucose uptake in skeletal muscle. Diabetes. 2007; 56(12): 2854-62
Taylor EB, An D, Kramer HF, Yu H, Fujii N, Roeckl KS, Bowles N, Hirshman MF, Xie J, Feener EP, Goodyear LJ. Discovery of TBC1D1 as an insulin-, AICAR-, and contraction-stimulated signaling nexus in mouse skeletal muscle. J Biol Chem. 2008.283(15): 9787-96
Fujii N, Ho RC, Manabe Y, Jessen N, Toyoda T, Holland WL, Summers SA, Hirshman MF, Goodyear LJ. Ablation of AMP-activated protein kinase {alpha}2 activity exacerbates insulin resistance induced by high-fat feeding of mice. Diabetes. 2008; 57(11): 2958-66






			Laurie J. Goodyear, Ph.D. Exercise Regulation of Glucose Transport in Skeletal Muscle It is well established that the performance of regular physical exercise results in numerous health benefits, including a reduced risk of developing type 2 diabetes. Physical exercise is also widely accepted as a clinically important modality to decrease blood glucose concentrations in patients with diabetes, due largely to an increase in the rate of glucose transport into the contracting skeletal muscles and an increase in insulin sensitivity in the period following exercise. Despite the profound clinical importance of the metabolic effects of exercise, until recently, there was little focus on understanding the underlying molecular mechanisms that mediate these responses. A major goal of the work in the Goodyear laboratory is to elucidate the mechanisms through which physical exercise increases glucose transport and insulin sensitivity in skeletal muscle. Work from the Goodyear laboratory has shown that muscle contractile activity increases glucose transport in muscle through intracellular signal transduction mechanisms that are distinct from that of insulin. The putative signals have long been elusive, but in recent years they have identified the AMP-activated protein kinase (AMPK) as a mediator of insulin-independent glucose transport in skeletal muscle. These studies had a major impact on biological research and contributed to worldwide interest in AMPK as a master regulator of metabolic and transcriptional functions in tissues and cells throughout the body, as well as identifying AMPK as a novel drug target for the treatment of diabetes. The lab’s work in the AMPK field is currently focused on elucidating downstream substrates for AMPK regulation of glucose transport and insulin sensitivity in skeletal muscle. To this end, the Goodyear laboratory has been at the forefront of studies investigating the rab GAP protein Akt substrate of 160 kDa (AS160), as well as TBC1D1, the AS160 paralog that is almost exclusively expressed in skeletal muscle. Their work also investigates the role of the AMPK kinase LKB1 in glucose and fatty acid metabolism, insulin signaling, and post-exercise insulin signaling in both skeletal muscle and heart. Studies from the Goodyear lab focused on defining contraction signals have revealed that AMPK is not the exclusive mediator of contraction-stimulated glucose transport. Therefore, an important focus of the lab is to elucidate the additional signaling systems that mediate insulin-independent glucose transport. Recently, work from the laboratory has led to the exciting discovery that the sucrose non-fermenting AMPK-related kinase (SNARK) is a novel, insulin-independent signal that mediates glucose uptake in skeletal muscle. In addition, they have evidence that SNARK and additional AMPK-related kinases may be important for many of the additional metabolic effects of exercise, and are currently working toward investigating the function of these proteins in skeletal muscle. These molecules are likely to draw considerable attention in the diabetes field in the near future. In addition to the acute effects of a single bout of exercise on muscle glucose metabolism, exercise training can lead to numerous chronic adaptations to skeletal muscle. These adaptations are fundamental for the salutary effects of increased physical activity on several human diseases including diabetes and congestive heart failure. The stimulus for these changes is thought to be initiated by each individual bout of exercise, as a single exercise session can significantly alter rates of gene transcription and protein synthesis. In working to understand how the contraction stimulus signals the transcriptional and protein synthetic processes, the Goodyear laboratory has discovered that exercise robustly alters the activity of numerous protein kinases including ERK, c-jun kinase, p38 kinase, Akt, GSK-3, and AMPK. In addition, they find that several novel proteins are robustly up regulated by exercise training, including SNARK and tribbles 3 (TRB3). Studies are underway to determine if the effects of chronic exercise to cause skeletal muscle remodeling involves the activation of these intracellular signal transduction pathways. To address all of these questions the laboratory uses a combination of molecular and physiological approaches including contraction of rodent skeletal muscles in vitro and in situ, knockout and transgenic mice, and a highly successful technique to overexpress foreign proteins into adult rodent skeletal muscle using electroporation. In conjunction with the Proteomics Core laboratory at Joslin, the Goodyear laboratory has developed methods to identify phosphorylation sites of endogenous skeletal proteins muscle using mass spectrometry. Furthermore, they have recently developed a novel imaging technique that can monitor the effects of muscle contraction on the localization and movement of fluorescently labeled proteins in the muscle fibers of live, anesthetized mice. These discoveries, made largely using animal models, have provided the basis for additional work on human subjects by the Goodyear lab and other groups around the world. All of these investigations should help define the molecular basis for the important adaptations that occur in skeletal muscle in response to exercise, and will have important ramifications for patients with metabolic and cardiovascular diseases. References: Kramer HF, Witczak CA, Fujii N, Hirshman MF, Jessen N, Taylor EB, Arnolds D, Sakamoto K, Goodyear LJ. Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle. Diabetes. 2006; 55(7): 2067-76 Kramer HF, Witczak CA, Taylor EB, Fuji N, Hirshman MF, Goodyear LJ. AS160 regulates insulin-and contraction-stimulated glucose uptake in mouse skeletal muscle. J Biol Chem. 2006; 281: 31478-31485 Witczak CA, Fujii N, Hirshman MF, Goodyear LJ. Ca2+/calmodulin-dependent protein kinase kinase-alpha regulates skeletal muscle glucose uptake independent of AMP-activated protein kinase and Akt activation. Diabetes. 2007; 56(5): 1403-9 Rockl KS, Hirshman MF, Brandauer J, Fujii N, Witters LA, Goodyear LJ. Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift. Diabetes. 2007; 56(8): 2062-9 Kramer HF, Fujii N, Witczak CA, Hirshman MF, Goodyear LJ. The calmodulin-binding domain of AS160 regulates contraction- but not insulin-stimulated glucose uptake in skeletal muscle. Diabetes. 2007; 56(12): 2854-62 Taylor EB, An D, Kramer HF, Yu H, Fujii N, Roeckl KS, Bowles N, Hirshman MF, Xie J, Feener EP, Goodyear LJ. Discovery of TBC1D1 as an insulin-, AICAR-, and contraction-stimulated signaling nexus in mouse skeletal muscle. J Biol Chem. 2008.283(15): 9787-96 Fujii N, Ho RC, Manabe Y, Jessen N, Toyoda T, Holland WL, Summers SA, Hirshman MF, Goodyear LJ. Ablation of AMP-activated protein kinase {alpha}2 activity exacerbates insulin resistance induced by high-fat feeding of mice. Diabetes. 2008; 57(11): 2958-66