home: research: centers and laboratories: cxr: muscle biology laboratory

Muscle Biology Laboratory

Dr. Gregory Cartee

1200 and 2200 CCRB
401 Washtenaw Ave.
Ann Arbor, MI 48109-2214
Phone: (734) 936-0281

Research Overview

The research in the Muscle Biology Laboratory is focused on skeletal muscle metabolism. We are especially interested in the modulation of glucose transport by exercise and calorie restriction (CR; consuming 60% of ad libitum uptake), and how these interventions are influenced by advancing age. Each of these interventions can lead to a substantial improvement in skeletal muscle insulin sensitivity, which is a significant benefit for health.

Exercise: Even with many years of regular exercise training, a substantial portion of the exercise effect on improved insulin sensitivity is attributable to the effects of the most recent exercise session. This acute exercise effect can last for several hours to several days. Insulin resistance (a lower than normal ability to clear blood glucose in the presence of normal blood insulin) is an essential defect in Type 2 Diabetes, and even in the absence of diabetes, insulin resistance is linked to many other pathologies, including atherogenesis, hypertension, cardiovascular disease, renal disease, some cancers, and cognitive dysfunction. For this reason, improved insulin sensitivity is an especially important health benefit of exercise. In addition, the improved insulin sensitivity has implications for exercise performance because it facilitates the restoration and supercompensation of muscle glycogen stores, thereby improving the capacity for subsequent exercise. Although it has been known for over twenty years that a single exercise bout can lead to a subsequent increase in insulin-stimulated glucose transport, the precise mechanisms that underlie this important benefit remain uncertain. Attempting to explain this elusive process is a primary goal of our research.

Akt Substrate of 160 kDa (AS160): Phosphorylation of the signaling protein called AS160 is the most distal insulin signaling event that has been linked to GLUT4 glucose transporter translocation in adipocytes. We recently demonstrated that AS160 found in skeletal muscle also becomes phosphorylated in response to either insulin or contractile activity, raising the possibility that this protein may represent a convergence between the insulin signaling and exercise/contraction pathways for increasing cell surface GLUT4 and glucose transport. We also found that in vivo exercise can elevate AS160 phosphorylation in skeletal muscle immediately post-exercise in the absence of insulin and 4 hours post-exercise in the presence of insulin. We are currently performing experiments to understand the regulation and function of AS160 in skeletal muscle.

Calorie Restriction (CR): A short period of reduced calorie intake (consuming ~60% of usual ad libitum intake for 20 days) can enhance insulin sensitivity for skeletal muscle glucose uptake. The figure above illustrates some of the key steps in the insulin signaling pathway that leads to increased glucose transport in skeletal muscle. We have found that Akt2 (in skeletal muscle, two isoforms of this protein are abundantly expressed: Akt1 and Akt2) is essential for the full-effect of short-term (20 days) calorie restriction on insulin-stimulated glucose transport. We are currently attempting to understand the signaling steps proximal and distal to Akt2 that are also important for this effect.

Current Projects

Mechanisms for Increased Insulin-Stimulated Glucose Transport after Acute Exercise

The precise mechanisms that underlie this important benefit of exercise remain uncertain. We are currently performing experiments to identify the mechanisms that underlie the effects of exercise/contraction on AS160 phosphorylation and to evaluate the role that AS160 plays in mediating exercise/contraction effects on glucose transport.

Mechanisms for Improved Insulin Sensitivity with Calorie Restriction

We have determined that with 20 days of calorie restriction (CR; consuming 60% of ad libitum, food intake), animals (rats or mice) have increased insulin-stimulated glucose transport (i.e., glucose entry into cells) in skeletal muscle with increased activation of insulin signaling proteins playing an key role. We are initiating new studies that will focus on understanding the mechanisms that account for improved insulin sensitivity with long-term CR (several months to several years) in adult and old animals.

In Vitro Simulation of Calorie Restriction: Effects on Skeletal Muscle Insulin Signaling and Action

We have established in vitro conditions for long-term incubation of rat skeletal muscle that allow us to study isolated muscles for up to 24 hours. Our primary aim is to determine if we can recapitulate the improvements in insulin-stimulated glucose transport and specific insulin signaling steps found with in vivo calorie restriction by simulating the effect of calorie restriction on extracellular glucose and/or insulin concentrations in this in vitro model.

Members

MBL members (l to r): Katsu Funai, Taku Hamada,
Robyn Odzark, and Ed Arias

Faculty:
    Gregory Cartee, Ph.D. (gcartee@umich.edu), Director
Research Associate II :
    Edward Arias, Ph.D. (edarias@umich.edu)
Postdoctoral Researcher:
    Naveen Sharma, Ph.D. (naveens@umich.edu)
Graduate Students:
    Abhi Bhatt (abhat@umich.edu)
    Carlos Castoreno (ccastore@umich.edu)
    Katsuhiko Funai (kfunai@umich.edu)
    George Schweitzer (ggschwei@umich.edu)
Undergraduate Students:
    David Blair (drblair@umich.edu)
    Reginald Hurtt, III (rhurtt@umich.edu)

Equipment

Tekan GENios Pro Microplate Reader (absorbance, fluorescence intensity, time-resolved fluorescence, fluorescence polarization, and luminescence)
Beckman Allegra 64R Benchtop Centrifuge;
Beckman DI530 Spectrophotometer;
Perkin Elmer Tri-Carb 2800 Liquid Scintillation Counter;
Alpha Innotech FluoroChem SP Imaging System;
Darkroom and Kodak 2000 Film Processor;
VWR –20oC Laboratory Freezer;
ThermoForma Refrigerator;
ThermoForma Chromatoagraphy Refrigerator;
Revco Laboratory Refrigerator;
2 ThermoForma –86oC Freezers;
BioRad Protean 3 Electrophoresis System;
BioRad Criterion Electrophoresis System;
BioRad Protein II xi 2D Electrophoresis System;
Owl Sci. A1 Gator Horizontal Electrophresis System;
BioRad Power Pac Basic & 1000 Power Supply;
Hoefer Sci. PS 500XT Power Supply;
2 Precision Shaking Baths;
Elga Purelab Water Purification System;
Caframo Homogenizer;
Mettler Toledo AB204-S Analytical Balance;
Toploader Balance;
Thermolyne Type 50800 Bench Rotator;
Fischer Sci. Clinical Rotator;
Eppendorf Mastercycler-S Thermocycler;
Fischer Sci. FS60H Sonicator;
Barnstead Autoclave;
Eppendorf 5415D Microcentrifuge;
Fischer Fume Hood;
Columbus Instruments Exer 3/6 Rodent Treadmill.

Links