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FACULTY

Sandy Martin


Professor

Sandy Martin, Professor

Cell and Developmental Biology
Ph.D., University of California at Berkeley, 1982

Research Interest

Define the molecular mechanisms responsible for tissue protection and reversible metabolic depression in hibernation by using high-throughput –omics analyses.

Contact

Office Location: RC-1 South, Room 12104

Mailing Address:

Mail Stop 8108​
12801 East 17th Avenue
Aurora, CO 80045

Phone: 303-724-3467
Fax: 303-724-3420

Email: Sandy.Martin@ucdenver.edu

Graduate Program Affiliations

Molecular Biology
Human Medical Genetics
Biomedical Sciences Program (BSP)
Medical Scientist Training Program (MSTP)​

The goal of our research is to discover the relationship between genome and phenome that underlies the remarkable physiology of hibernation. Hibernators have naturally solved many of the intractable problems that plague human medicine; we believe that decoding these solutions offers unparalleled opportunity to design new approaches that will mitigate and reverse damage from cardiac arrest, stroke, trauma, obesity, and from bone and muscle disuse atrophy. Our model organism is the thirteen-lined ground squirrel, which hibernates for about half the year. During hibernation, these remarkable mammals cycle their physiology between two extremes, torpor and arousal, with the vast majority of the time spent in torpor. To enter torpor, metabolic rate is dropped to just 5% of basal in concert with severe depression of heart and respiratory rates. Core body temperature then plummets to near freezing, further enhancing and stabilizing the metabolic depression; this extreme physiology persists for ~two weeks and then is reversed rapidly and spontaneously, bringing core temperature and metabolism back to more typical mammalian homeostatic values where they remain for about 12 hours before the animal cycles back into torpor. The process of arousing from torpor and rewarming the body more than 30◦C takes just two hours, uses only endogenous mechanisms to generate heat (first non-shivering, then shivering thermogenesis), and occurs via an internal timing mechanism without environmental warming. In sharp contrast to hibernation, during the remainder of the year these animals maintain high metabolism and body temperature continuously and do not enter torpor. Annually and prior to the onset of winter, the animals also become obese. They suddenly stop eating, and switch to burning rather than storing fat, relying on this stored fuel throughout the six months of winter hibernation. The seasonal changes that distinguish the hibernation and active phases of their annual cycle include enhanced tissue protection in organs throughout the body during winter, and transient (notably, reversible) obesity. In torpor-arousal cycles, largely unknown mechanisms protect against ischemia-reperfusion damage despite intense metabolic activation during the short, rapid rewarming phase. To gain insight into the genetic and biochemical mechanisms underlying this remarkable physiology we have exploited the key feature of timing in both the seasonal cycle and the torpor-arousal cycle by collecting a tissue bank from ~ 200 precisely- timed animals in different stages of both cycles. The bank has provided robust information about protein and metabolite changes in sync with hibernation physiology, but we have just begun to scratch the surface of what this unique resource can reveal about this extraordinary phenotype. Ongoing efforts are directed towards understanding mechanisms of neuroprotection as well as metabolic control and body weight homeostasis using RNA-seq and other modern genomics methodologies.

 

Fig1.tif
Figure 1.Body temperature dynamics in hibernation and sampling timepoints for our studies. From the active, homeothermic portion of the year (A), early August and April, when animals are fat and lean, respectively. From the hibernation season (B), the indicated times of entrance (Ent), early and late torpor (ET, LT), early and late arousing (EAr, Lar) and interbout aroused (IBA), with timing of sample collection based on body temperature from implanted devices.

 

Fig2.tif

Figure 2. Schematic depicting the torpor-arousal cycles (dark blue and green, respectively) of hibernation
embedded within just the hibernation phase (blue) of the seasonal cycle.

 



Grabek, K.R., Diniz Behn, C., Barsh, G.S., Hesselberth, J.R. and Martin, S.L. Enhanced stability and polyadenylation of select mRNAs support rapid thermogenesis in the brown fat of a hibernator. (2015) eLIFE 4:e04517.

Hindle, A.G., Otis, J.P., Epperson, L.E., Hornberger, T.A., Goodman, C.A., Carey, H.V., and Martin, S.L. Prioritization of skeletal muscle regrowth for emergence from hibernation. (2015) J Exp Biol 218:276-284.

Grabek, K.R., Martin, S.L. and Hindle, A.G. (2015) Proteomics approaches shed new light on hibernation physiology. J Comp Physiol B 185:607-627.

van Breukelen, F. and Martin, S.L. (2015) The hibernation continuum: Physiological and molecular aspects of metabolic plasticity in mammals. Physiology (Bethesda, Md) 30:273-281.

Lanaspa, M.A., Epperson, L.E., Li, N., Cicerchi, C., Garcia, G.E., Roncal-Jimenez, C.A., Trostel, J., Jain, S., Mant, C.T., Rivard, C.J., Ishimoto, T., Shimada, M., Sanchez-Lozada, L.G., Nakagawa, T., Jani, A., Stenvinkel, P., Martin, S.L., and Johnson, R.J. (2015) Opposing activity changes in AMP deaminase and AMP-activated protein kinase in the hibernating ground squirrel. PLoS ONE 10:e0123509.

Hindle, A.G. and Martin, S.L. (2014) Intrinsic circannual regulation of brown adipose tissue form and function in tune with hibernation. Am J Physiol Endocrinol Metab 306:E284-99.

Hindle, A.G., Grabek, K.R., Epperson, L.E, Karimpour-Fard, A. and Martin, S.L. The liver proteome in hibernating ground squirrels is dominated by metabolic changes associated with the long winter fast. (2014) Physiol Genomics 46:348-61.

Martin, S.L. and Yoder, A.D. (2014) Theme and variations: heterothermy in mammals. Integrative and Comparative Biology, doi: 10.1093/icb/icu085.

Martin, S.L. (2014) Intrinsic circannual rhythm controls protein dynamics in a hibernator to support rapid heat production. Temperature 1:2, 80-81.

Hindle, A.G. and Martin, S.L. (2013) Cytoskeletal regulation dominates temperature-sensitive proteomic changes of hibernation in forebrain of 13-lined ground squirrels. PLoS ONE 8: e71627.

Jani, A., Martin, S. L., Jain, S., Keys, D. and Edelstein, C.L. (2013) Renal adaptation during hibernation.  Am J Physiol - Renal Physiology 305:F1521-F1532.

Jani, A., Orlicky, D.J., Karimpour-Fard, A., Epperson, L.E., Russell, R.L., Hunter, L.E., and Martin, S.L. (2012) Kidney proteome changes provide evidence for a dynamic metabolism and regional redistribution of plasma proteins during torpor-arousal cycles of hibernation. Physiol Genomics 44:717-727.

Carey, H.V., Martin, S.L., Horwitz, B.A., Yan, L., Bailey, S.M., Podrabsky, J., Ortiz, R.M., Storz, J.F., Wong, R.P., and Lathrop, D.A. (2012) Elucidating Nature’s Solutions to Heart, Lung, and Blood Diseases and Sleep Disorders. Circ. Res. 110, 915-921.

Epperson, L.E., Karimpour-Fard, A., Hunter, L.E. and Martin, S.L. (2011) Metabolic cycles in a circannual hibernator. Physiol. Genomics 43:799-807. 

Hindle, A.G., Karimpour-Fard, A., Epperson, L.E., Hunter, L.E., and Martin, S.L.(2011) Skeletal muscle proteomics: Carbohydrate metabolism oscillates with seasonal and torpor-arousal physiology of hibernation. Am J Physiol Regul Integr Comp Physiol, 301:R1440–R1452.

Jani, A., Epperson, E., Martin, J., Pacic, A., Ljubanovic, D., Martin, S.L., and Edelstein, C.L. (2011) Renal protection from prolonged cold ischemia and warm reperfusion in hibernating squirrels. Transplantation, 92:1215-1221.

Grabek, K.R., Karimpour-Fard, A., Epperson, L.E., Hindle, A.G., Hunter, L.E., and Martin, S.L. (2011) A multi-state proteomics analysis reveals novel strategies used by a hibernator to precondition the heart and conserve ATP for winter heterothermy. Physiol Genomics 43: 1263-1275.