Skeletal muscle metabolic dysfunction and atrophy are prominent features of a number of devastating diseases, including diabetes and cancer, and can also occur in healthy individuals in response to aging and inactivity. Intracellular Ca2+ is a key regulator of many processes in skeletal muscle, including metabolism and growth, yet surprisingly the signaling mechanisms by which Ca2+ regulates these critical functions remain largely unknown. Recent work from my postdoctoral studies has identified the Ca2+-sensitive serine/ threonine kinase, Ca2+/calmodulin-dependent protein kinase kinase alpha (CaMKKalpha), as a novel regulator of contraction-induced glucose transport in skeletal muscle. Importantly, we found that CaMKKalpha regulates glucose transport independent of the AMP-activated protein kinase, a signaling protein already implicated in this process. Thus, the downstream mechanism by which CaMKKalpha mediates glucose transport is not known, and the identification of this substrate is the focus of Specific Aim 1. In addition, exciting preliminary data from my studies suggest a positive role for CaMKKalpha in the regulation of skeletal muscle mass via the mammalian target of rapamycin (mTOR) signaling cascade, a pathway that regulates protein synthesis. Thus, the goal of Specific Aims 2 and 3, the focus of my independent research studies, is to determine the role of CaMKKalpha in the regulation of skeletal muscle growth and protein synthesis. The significance of this work is that elucidation of the signaling proteins involved in these key processes should lead to the development of new treatments for muscle metabolic and wasting disorders associated with many diseases, including diabetes and cancer. PUBLIC DESCRIPTION: Impaired metabolic function and loss of muscle mass are prominent features of a large number of devastating diseases, including diabetes and cancer, and can also occur in healthy individuals in response to aging and inactivity. Our goal is to determine the role that the intracellular protein, Ca2+/calmodulin-dependent protein kinase kinase alpha, plays in the regulation of skeletal muscle glucose metabolism and growth. Understanding the pathways involved in these key processes should lead to the development of better pharmaceutical treatments for muscle metabolic and wasting disorders associated with numerous diseases, including diabetes and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Career Transition Award (K99)
Project #
5K99AR056298-02
Application #
7677348
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Boyce, Amanda T
Project Start
2008-09-01
Project End
2010-12-31
Budget Start
2009-07-01
Budget End
2010-12-31
Support Year
2
Fiscal Year
2009
Total Cost
$89,060
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Ferey, Jeremie L A; Brault, Jeffrey J; Smith, Cheryl A S et al. (2014) Constitutive activation of CaMKK? signaling is sufficient but not necessary for mTORC1 activation and growth in mouse skeletal muscle. Am J Physiol Endocrinol Metab 307:E686-94
Hinkley, J Matthew; Ferey, Jeremie L; Brault, Jeffrey J et al. (2014) Constitutively active CaMKK? stimulates skeletal muscle glucose uptake in insulin-resistant mice in vivo. Diabetes 63:142-51
Toyoda, Taro; An, Ding; Witczak, Carol A et al. (2011) Myo1c regulates glucose uptake in mouse skeletal muscle. J Biol Chem 286:4133-40
Witczak, Carol A; Jessen, Niels; Warro, Daniel M et al. (2010) CaMKII regulates contraction- but not insulin-induced glucose uptake in mouse skeletal muscle. Am J Physiol Endocrinol Metab 298:E1150-60
Treebak, Jonas T; Taylor, Eric B; Witczak, Carol A et al. (2010) Identification of a novel phosphorylation site on TBC1D4 regulated by AMP-activated protein kinase in skeletal muscle. Am J Physiol Cell Physiol 298:C377-85
Rogers, Nicole H; Witczak, Carol A; Hirshman, Michael F et al. (2009) Estradiol stimulates Akt, AMP-activated protein kinase (AMPK) and TBC1D1/4, but not glucose uptake in rat soleus. Biochem Biophys Res Commun 382:646-50