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grizzly bears exhibit low levels of shuddering (5 o C (Brian Barnes, personal communication), but thebears used by Donahue, et. al. rarely drop past this threshold. Therefore it is probablethat another mechanism for maintaining balanced bone formation and resorption isresponsible.As stated earlier, it is possible that bears maintain balanced bone resorption andformation during hibernation by inhibiting osteoblast and osteocyte apoptosis. Osteocyteapoptosis precedes bone loss in unloaded mice, and attenuating osteocyte andosteoblast apoptosis with injections of PTH will inhibit this bone loss [48-51, 56]. It ispossible that osteoblast and/or osteocyte apoptosis is required for disuse-induced boneloss, although currently no studies have explored this idea. However, a study with apan-caspase inhibitor in ovariectomized mice demonstrates that caspase activation isrequired for bone loss in this model of osteoporosis [162]. Many hormones are known toregulate osteoblast and osteocyte apoptosis, the most notable of which are PTH [49, 55]and steroid hormones like estrogen [57]. If concentrations of anti-apoptotichormones increase during hibernation in bears, bone loss may be preventedduring this period of extended disuse.Apoptosis-inducing threats are prevalent in hibernating animals—these includeprolonged drops in temperature, substantial decreases in oxygen transport to tissues,metabolic acidosis, anorexia, and disuse—yet hibernating animals do not seem to sufferfrom large-scale apoptotic response (for review see: [163]). Despite this qualitativeobservation that hibernating animals seem resistant to apoptosis, few studies havespecifically quantified apoptosis in tissues from hibernating animals. Although theexpression of the anti-apoptotic protein Akt increases in the gut of hibernating groundsquirrels, the amount of activated (i.e. phosphorylated) Akt during winter remainsunaffected compared to summer values [45]. However, this study found a decrease inphosphorylated Akt in the gut mucosa of torpid ground squirrels compared to inter-boutarousal squirrels [45]. Reduced Akt phosphorylation has also been observed in the16
ain, heart, and femoral muscle of hibernating ground squirrels compared to winterwarm-adapted (active) squirrels [164]. Similarly, levels of phosphorylated Akt in thebrain, kidney, liver, and white adipose tissue of torpid bats was lower than levels in batsaroused from hibernation [165]. This hypophosphorylation of Akt may not increaseapoptosis in the hibernating animal. It is possible that reduced levels of phosphorylatedAkt may act through FoxO transcription factors to induce a state of hypometabolismwhich protects cells from glucose and oxygen deprivation [164, 166, 167]. Thus, in thelow-energy environment of hibernation, hypophosphorylation of Akt may prevent celldeath, rather than promote it.A few studies have explored the effects of hibernation on TUNEL staining. Theseminiferous epithelium of cold adapted (hibernating) Syrian hamsters had more TUNELpositive cells than warm adapted (active) hamsters [168]. TUNEL positive cell numbersincreased in the brains of hibernating frogs (Rana esculenta) compared to summeractivefrogs [169]. The number of TUNEL positive enterocytes in the midvillus region ofsummer squirrels was higher than the number in winter (hibernation) squirrels [45]. Thistrend in TUNEL positive cells increased with time as winter progressed, such that latehibernationsquirrels had the highest number of TUNEL positive cells [45]. In contrast,this study also demonstrated that caspase-3 activation in the gut of hibernating groundsquirrels decreased compared to active squirrels, and no DNA laddering was present inhibernation gut tissue [45]. These data suggest that TUNEL stains in hibernating tissuesmay be inaccurately interpreted as an increase in apoptosis. It is possible that theincrease in TUNEL positive cells during hibernation may be due to an accumulation ofdamaged DNA during this season [45]. Therefore, it is unclear from these studieswhether apoptosis is generally inhibited during hibernation, though the study in guttissue would suggest a suppression of apoptotic signaling overall [45], and qualitativeassessments of tissue survival in hibernation suggest that apoptosis-mediated tissuedamage is minimized at this time [163]. It is possible that an alleviation of osteoblastand osteocyte apoptosis during hibernation (possibly through circulation of antiapoptotichormones) combats bone loss.17
Page 1 and 2: EXPLORATION OF THE ROLE OF SERUM FA
Page 3 and 4: Table of contentsIndex of Figures .
Page 5 and 6: Chapter Four - Attempts to find an
Page 7 and 8: Index of figures1.1. Simplified sch
Page 9 and 10: 6.17. Longitudinal analysis of OPG
Page 11 and 12: 6.49. Longitudinal analysis of ColI
Page 13 and 14: A.2. Complete list of BSALP correla
Page 15 and 16: List of abbreviationsα-MEM. Alpha-
Page 17 and 18: PCR. Polymerase chain reactionPer1
Page 19 and 20: G2/M checkpoint. The point in the c
Page 21 and 22: Species names13-lined ground squirr
Page 23 and 24: Chapter One - Background and signif
Page 25 and 26: 1.3 Bone turnover is unbalanced dur
Page 27 and 28: pro-apoptosis regulator BAX. An imp
Page 29 and 30: low-dose administration of parathyr
Page 31 and 32: decrease in bone trabecular thickne
Page 33 and 34: experience periodic arousals in whi
Page 35 and 36: ears must have evolved a mechanism
Page 37: 1.7.6 Hypothesis 2: OCN interacts w
Page 41 and 42: Hypothesis 3a: Serum concentrations
Page 44: were released. Behavior indicating
Page 47 and 48: 2.3 ResultsSerum activity of the bo
Page 49 and 50: (p
Page 51 and 52: post-hibernation sampling in the be
Page 53 and 54: also unclear whether ucOCN may affe
Page 55 and 56: atios of intact to fragmented OCN m
Page 57 and 58: Table 2.3—Bone marker “seasonal
Page 59 and 60: Table 2.7—Chemistry panel “seas
Page 61 and 62: ABNormalized BSALPBSALP (U/L)CO N D
Page 63 and 64: Total Calcium (mg/dL)A1.21.151.11.0
Page 65 and 66: ABTotal OCN (ng/mL)150100500O N D J
Page 67 and 68: Adiponectin (ng/mL)AB40003500300025
Page 69 and 70: ABNormalized InsulinInsulin (μU/mL
Page 71 and 72: surrounding and encompassing hibern
Page 73 and 74: decreased from 788+30 ng/mL in preh
Page 75 and 76: 120-122]. Most small hibernators ar
Page 77 and 78: ears. Similarly, serum NPY increase
Page 79 and 80: Table 3.2—Serum factor longitudin
Page 81 and 82: Leptin (ng/mL)ABO N D J F M A M O N
Page 83 and 84: Norepinephrine (ng/mL)A807060504030
Page 85 and 86: IGF‐1 (ng/mL)AN D J F M A MB10009
Page 87 and 88: 2008. Samples were collected as des
Page 89 and 90:
sampling points. It is possible to
Page 91 and 92:
C‐Terminal PTH (Relative)AB504030
Page 93 and 94:
Chapter Five — Serum from hiberna
Page 95 and 96:
Synergy HT Multi-Detection Micropla
Page 97 and 98:
gene specific primers and 12.5 μL
Page 99 and 100:
involved in the reduced caspase-3/7
Page 101 and 102:
hibernation cycles without problem
Page 103 and 104:
filtered seasonal bear serum and fo
Page 105 and 106:
which is dependent upon caspase-3 a
Page 107 and 108:
Caspase‐3/7 ActivityO N D J F M A
Page 109 and 110:
6Caspase‐3/7 Activity54321**0Vehi
Page 111 and 112:
ABCaspase‐3/7 Activity9876543210*
Page 113 and 114:
eyond the G1/S checkpoint, thus ind
Page 115 and 116:
ears, it is possible that tissue se
Page 117 and 118:
PTH1R, RANKL, Runx2, Smurf1, TLR4,
Page 119 and 120:
factors Runx2 and OCN also increase
Page 121 and 122:
Table 6.3—Gene expression 3 hour
Page 123 and 124:
Table 6.5—Gene expression 6 day d
Page 125 and 126:
Cyclin D1 Gene ExpressionO N D J F
Page 127 and 128:
Smurf1 Gene ExpressionO N D J F M A
Page 129 and 130:
BAK Gene ExpressionO N D J F M A MM
Page 131 and 132:
M‐CSF Gene ExpressionO N D J F M
Page 133 and 134:
Per1 Gene ExpressionO N D J F M A M
Page 135 and 136:
Akt Gene ExpressionO N D J F M A MM
Page 137 and 138:
Bcl‐2 Gene ExpressionO N D J F M
Page 139 and 140:
Cyclin D1 Gene ExpressionO N D J F
Page 141 and 142:
OPN Gene ExpressionO N D J F M A MM
Page 143 and 144:
2PTH1R Gene Expression1.510.50O N D
Page 145 and 146:
TLR4 Gene ExpressionO N D J F M A M
Page 147 and 148:
Bcl‐2 Gene ExpressionO N D J F M
Page 149 and 150:
OCN Gene ExpressionO N D J F M A MM
Page 151 and 152:
PTH1R Gene ExpressionO N D J F M A
Page 153 and 154:
TLR4 Gene ExpressionO N D J F M A M
Page 155 and 156:
condition in renal patients in whic
Page 157 and 158:
hibernation. This report brings to
Page 159 and 160:
14. Kaneps, A.J., S.M. Stover, and
Page 161 and 162:
41. Chowdhury, I., B. Tharakan, and
Page 163 and 164:
68. Ashe, M.C., et al., Bone geomet
Page 165 and 166:
95. Perrien, D.S., et al., Aging al
Page 167 and 168:
122. Lesser, R.W., et al., Renal re
Page 169 and 170:
151. Confavreux, C.B., R.L. Levine,
Page 171 and 172:
178. Toribara, T.Y., A.R. Terepka,
Page 173 and 174:
206. Luo, X.H., et al., Adiponectin
Page 175 and 176:
233. Florant, G.L., et al., Fat-cel
Page 177 and 178:
259. Bhasin, S., et al., Older men
Page 179 and 180:
284. Miura, M., et al., A crucial r
Page 181 and 182:
Appendix A—Complete tables of cor
Page 183 and 184:
Table A.5—Complete list of ionize
Page 185 and 186:
Table A.7—Complete list of adipon
Page 187 and 188:
Table A.12—Complete list of norep
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