Research has shown that black bears (Ursus americanus) are able to defy some basic rules of mammalian physiology. Months of inactivity would lead to disastrous bone thinning in humans, but leaves bears' bones unharmed. Although bears do not move their large muscles for more than 100 days they actually increase their lean body mass in the den. Bears do not urinate during months of hibernation but their bodies show no build up of urea, a toxic waste product of protein metabolism normally eliminated by the kidneys. Hibernating bears seem to be able to make use of bone degradation products to build new bone and urinary wastes to make protein. Researchers hope to use chemicals from the bear to treat human and animal suffering from osteoporosis and from kidney failure. In mammals mechanical unloading of bone causes an imbalance in bone formation and resorption leading to bone loss and increased fracture risk. Black bears are inactive for several months during hibernation, yet bone mineral content and strength do not decrease with disuse or aging. 1
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The black bear spends 4-7 months each winter hibernating in its den (Beck 1991). Bears do not arouse during the winter to eliminate metabolic waste or eat and drink during hibernation (Nelson et al 1973, 1983; Harlow et al 2004) but they are capable of initiating a profound locomotor response to a threat or disturbance even while in a state of mild hypothermia. Bears demonstrate unimpaired locomotor function during the winter and are also able to sustain walking and running through heavy snow without noticeable strength loss or fatigue (T.D.I Beck, personal observation of several hundred denned bears). This apparent retention of locomotor function is remarkable considering that the bear is confined to a small space with limited mobility, has no access to food or water, and maintains a body temperature that is only a few degrees below its activity range for an entire winter (Nelson et al. 1973: Harlow et al. 2004).
Collected evidence supports the hypothesis that black bears have evolved biological mechanisms to mitigate or avoid the adverse effects of disuse on bone and/or have better compensatory mechanisms to more rapidly recover from disuse osteoporosis (Floyd et al 1990; Pardy et al., 2004). 2
The hibernating black bears are an excellent model for disuse osteoporosis in humans because it is a naturally occurring large animal model. Bears and humans have similar lower limb skeletal morphology and walk plantigrade like humans. Age related changes of material properties, histology, mineral content and whole bone bending strength of black bear cortical bone have been quantified and used to make inferences about how bears' bones are affected by disuse.
Disuse osteoporosis occurs in patients with spinal cord injuries, patients confined to prolonged bed rest, and astronauts exposed to microgravity during spaceflight (Leblanc et al 1990; Garland et al 1992; Cllet et al 1997; Daurt et al 2000; Vico et al 2000).
During remobilization, the recovery of the bone lost during disuse is slow and may nott be complete (Lindgren and Mattsson 1977 Jaworski and Uhthoff 1986; Leblanc at al 1990; Vico et al 2000). Bone can be continued to be lost during rmobilization (Trebacz 2001). Rapid increases in bone resorption and sustained decreases in bone formation contribute to bone loss during limb immobilisation by casting, tetonomy, or neurectomy (Weinreb et al 1989; Rantakokko et al 1999).
There is massive investigation into the mechanisms and compounds that enable bears to achieve these physiological marvels. If such compounds also worked in humans, it could have a vest market among millions of older people and animals who suffer from bone thinning and the inevitable fractured that result. Although several treatments for osteoporosis are now available, they mainly work to inhibit further bone destruction. They do nothing to accelerate the growth of new bone. Researchers have been hoping to find a systemic hormone that regulates bone growth in humans, but as yet it is not known if one exists. The bears' ability to maintain bone and lean muscle mass is an interesting physiological phenomenon, more research is needed.
Bears are making small amounts of urine all winter long but somehow, instead of accumulating in the bladder, the urine and nitrogen containing urea were reabsorbed across the bladder wall. To trace the fate of urea that was disappearing from the bladder, researchers synthesized urea containing radioactive molecules and injected them into hibernating bears. To their surprise, the radioactive urea vanished and the radioactivity began turning up in various proteins, including albumin, which helps maintain blood volume and neurotransmitters. The hibernating bears had taken apart the urea and used its components to make amino acids to be used in building proteins. The energy for this astounding recycling mechanism is provided by the bear's fat stores. Researchers believe bears are probably the only animal that can split urea in the body.
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There has been great debate about the classification and the concept of hibernation in regards to bears and their seasonal activity patterns. Most animals that sleep through the winter drop their body temperature drastically and cut nutritional needs sharply during hibernation; "deep hibernators" like squirrels and woodchucks spend winter limp and defenceless. But bears lower their body temperature only slightly, exhibiting mild hypothermia of only 2-5 degrees Celsius below normal and do not arouse unless disturbed (Nelson et al. 1973; Harlow et al 2004). Small mammal hibernators decrease their body temperature 30-35 degrees below normothermia but arouse every 1-3 weeks to urinate, defecate and even drink water, depending on the species (Harlow and Menkens 1985; Barnes 1989; Boyer and Barnes 1999).
Gluconeogenic demands associated with repeated arousal from multiple torpor bouts necessitate protein catabolism (Burlington and Klain 1967; Galster and Morrison 1975), which may account for measurable losses of muscle protein in some small mammal hibernators (Yacoe 19843; Steffen et al 1991; Wickler at al. 1991). However, while repeated arousal bouts may induce protein catabolism, it is believed that they may also be important to facilitate the maintenance of skeletal muscle integrity as a result of vigorous shivering episodes (Rourke et al. 2004a, 2004b). Black bears exhibit subtle muscular activity that does not result in complete arousal (Harlow et al 2004) and thereforE would not require substantial protein catabolism. This is believed to contribute to the greater strength retention by bears than expressed by traditional disuse atrophy models and similar or greater strength retention by bears than by small-mammal deep-hibernating species exposed to prolonged periods of reduced activity and food intake.
Sleeping/hibernating bears have a unique mechanism for regulation calcium. Based on blood samples collected from anaesthetized bears before, during and after hibernation, calcium levels in the blood are fairly constant. This is surprising since the bone of other mammals including mammals inevitably thins when it does not carry weight for long periods, loosing calcium into the blood. Osteoporosis is thought to result from an imbalance between bone production by cells called osteoblasts and bone destruction by another group of cells called osteoclasts. Bone is constantly being formed and destroyed by these two groups of cells, which in periods of normal activity balance each other. During long periods of intense exercise, bone formation out steps destruction and bone mass increases. But in periods of prolonged rest, such as when a leg is in a cast, the bone building osteoblasts slow down, even cease to function and the bone then become brittle.
Such thinning causes problems for patients at prolonged bed rest, who may lose up to a quarter of their bone mass in half a year of rest, as well as astronauts in the weightlessness of space, who lose up to 2 percent of their bone for every month that they fly. Deep hibernators also loose bone as they lie dormant. The calcium that leeches into the blood as the bone degrades is eliminated in the urine; even deep hibernators arouse occasionally to relieve themselves. Bone specimens reveal that bears do not lose any bone mass despite months of rest, even in hibernation their osteoblasts continue to lay down new bone. The calcium lost from bone into the blood from one part of the skeleton can subsequently be used to build new bone at another.
Muscle disuse atrophy is typically modelled on four systems: microgravity (Edgerton et al. 1995; Lambertz et al 2000), bed rest (Dudley et al 1989; LeBlanc et al 1992; Berg et al 1997; Widrick et al 1998; Alkner and Tesch 2004) limb immobilization by casting (Hortobagyi et al 2000; Thom et al 2001; Krawiec et al 2005) or by suspension (Berg et al 1991; Ploutz-Snyder et al 1996) and denervation with spinalization or spinal isolation (Talmadge et al 1995, 1999 Haddad 2003). The response is similar for all models and is predominantly described in rats, mice, and humans (reviewed in Baldwin and Haddad 2001 Adams et al 2003).
Uniformly, all atrophy models show a profound decrease in myofibrillar and sarcoplasmic protein (Larsson et al. 1996; Berg et al. 1997; Gamrin et al. 1998; Lecker et al 1999; reviewed in Lecker and Goldberg 2002) and whole-muscle cross sectional area and mass (LeBlanc et al 1992; Narici et al 1997; Kraweic et al 2005; reviewd in Adams et al 2003) as well as fiber size (Edgerton et al 1995; Hortobagyi et al 2000; Rittiweger et al 2005. Atrophy models are also characterized by a loss of skeletal muscle strength (Dudley et al 1989; Hortobagyi et al 2000; Roy et al 2002; review in Adams et al 2003) and reduced aerobic capacity and resistance to fatigue (McDonald et al. 1992; Zhan and Sieck 1992). In addition, under some conditions, the time course of in vivo muscle contractile properties may be altered as a result of changed myosin heavy chain (MHC) isoforms (reviewed in Baldwin and Haddad 2001; Caiozzo 2002) or changed sarcoplasmic reticulum calcium kinetics (Shulte et al. 1993) in response to unloading. 3
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Skeletal muscle of adult mammals is polymorphic. Muscle fibers generally referred to as slow-twitch oxidative predominantly contain the slow-twitch type 1 MHC isoforms, while fast-twitch glycolytic fibers contain greater, yet variable, amounts of the faster 2x or 2b MHC isoforms (reviewed in Caiozzo 2002). The relative expression of these MHC isoforms in the muscle is subject to resculpturing as a result of atrophy. Skeletal muscle atrophy affects predominantly slow-twitch oxidative rather than fast-twitch glycolytic fibers (humans not included) (Thomason and Booth 1990; Fitts et al 2000, 2001). Atrophy is associated with a loss of type 1 MHC slow isoform composition of skeletal muscle (reviewed in Baldwin and Haddad 2001). Changes in MHC composition have complex effects on muscle function (reviewed in Cioazzo 2002), atrophy models, including unloading, spaceflight, immobilation, limb suspension and denervation suggest that partial or complete conversion of slow to fast or slow to fast MHC transformations (Desplanches et al 1987; Anderson et al 1999; review in Baldwin and Haddad 2001). Atrophy can result in altered whole-muscle contractile parameters (Caiozzo et al 1998; Haddad 2003). These include contraction time, half-relaxation time, and associated measurements that evaluate the time course of muscle movements. These contractile properties could serve as further indicators of compromised whole-muscle function.
Black bears are completely fasted during winter, and even though they do not undergo weightlessness, casting, or denervation, they do experience limited mobility. Their strength loss during this time is markedly lower than that of animal models subjected to only a single perturbation, much less a combination of food deprivation and immobility that induces muscle atrophy. Despite the bears' abilities the protein sparing effect is not complete, metabolic demands for gluconegenic precursors and tricarboxcylic acid cycle intermediates necessitate a moderate amount of protein catabolism (Bintz et al. 1979; Yacoe 1983). Small losses of protein from several muscle groups may be sufficient in meeting the denning bears' metabolic demands for protein without severely compromising muscle function. This small loss of protein is reported to be approximately 7.6% of total body protein in black bears (Harlow et al 2002), with evidence of very limited protein loss from black bear hind limb muscles. It is very well documented that protein loss, as a result of either limited mobility or fasting, varies between muscle groups (Li and Goldberg 1976; Gogia et al. 1988; LeBlanc et al. 1992).
By utilizing small amounts of protein from specific skeletal muscles while completely conserving protein in others and at the same time utilizing alternate potentially labile protein reserves, the denned bear is able to meet metabolic demands without severely compromising strength during extended fasting and limited mobility. Equally important to mobility is the retention of protein within the sarcoplasmic reticulum for calcium release and uptake (Schulte et al 1993; reviewed in Allen and Westerblad 2001). In addition, loss of vascular smooth muscle and changes in myoglobin content and enzyme activity are also associated with changes in muscle fiber function.
Fatigue results from decreased oxygen delivery (McDonald et al. 1992), limited ATP availability , or reduced calcium release from sarcoplasmic stores (Allen et al 1995; Favero 1999). Muscles that show a reduced oxidative capacity or loss of slow-oxidative fibres as a result of atrophy will fatigue more rapidly (Booth 1977; Fell et al. 1985; Witzmann et al. 1992). Black Bears appear to sustain only moderate loss of fatigue resistance over the winter. At the end of 110 days of fasting and confinement, bears still exhibited a profile of 29% and 44% decrease in force with 1 min of 3-Hz stimulus, respectively. This increased susceptibility measured in late winter is not one that should severely limit locomotor performance. After 110 days of fasting and limited mobility imposed by denning, bears still exhibited a fatigue profile to that of healthy, active, fed humans.
Mammalian skeletal muscle is heterogenous composition of slow-twitch type 1 and fast-twitch type 2 fibers with contractile properties that differ in part because of their MHC expression. Unloading or immobilization causes atrophy as well as an increase in the proportion of fast relative to slow MHC isoforms, measured at both the single fiber and whole-muscle levels (Caizzo et al. 1998; reviewed in Baldwin and Haaddad 2001; Caizzo 2002). A notable type 1 to type 2 transition is evident in spaceflight (Caiozzo et al 1996), and hindlimb suspension (Thomas et al. 1987; reviewed in Baldwin and Haddad 2001) with up to an 80% decrease in MHC in slow twitch muscles after 15 days of spinal isolation (Haddad et al 2003). This may result in a greater number of fibers in a muscle expressing type 2 fast MHC isoforms as a result of unloading and a tendency for that muscle to exhibit more fast-glycolytic characteristics and less resistance to fatigue (Diffeet at al 1991; reviewed in Caiozzo 2002).
None of seven whole-muscle contractile properties- contraction time, half-maximal value time, half maximum duration, time to peak force development and decay, and rate of force development and decay- were altered in response to anorexia and confinement imposed by 110 days of confinement of denning bears. 3
Bears rely heavily on fat as an energy source during hibernation (Nelson et al 1973; Harlow et al 2002). They are capable of extremely difficult nitrogen sparing during winter; they are known to recycle almost 100% of the urea produced from protein catabolism (Barboza et al 1997) which may be used to resynthesise lost skeletal muscle (Nelson et al 1973). Conservation of some muscle groups may occur preferentially over others. Nonmyofibrillar protein reserves may be used, which would spare structural skeletal muscle properties. These sources may include plasma protein, extracellular matrix, and smooth muscle or organ tissue. (Rourke et al 2006). Small-mammal hibernators may retain or even increase MHC 1 slow isoforms through heavy muscle contraction during arousal. Bears may undergo repeated isometric and shivering movements while in the den (Harlow et al 2004). These relatively moderate movements are sufficient to limit muscle atrophy (Ritweger et al 2005) and retain strength (Gogia et al 1988). And may be employed by hibernating black bears to preserve muscle integrity. (Harlow et al 2004).
To make it through the long winters in their dens, black bears rely on a kind of internal recycling. As their bones leak calcium while they sleep, they re-use it to lay down new bone, preventing osteoporosis. Rather than ridding themselves of wastes by urinating, they re-use the toxic materials to create essential proteins. In humans, about 25 percent of urea produced by metabolism is recycled to new proteins by bacteria in the intestine, and the rest must be excreted in the urine. But resting bears reprocess all their urea. It is also said that the bear recycles urea faster than it makes it, so the animal ends up with a little more protein at the end of denning than it had to begin with. The application to human and animal health problems can be seen. Patients with kidney failure make more urea than their kidneys can filter out. The appeal of a fat burning mechanism for a society battling an obesity epidemic would astronomical. Osteoporosis treatment would lead to reduction in fractures and less occurrences of hospitalization. Any one of these applications would lead to a greater improvement in the quality of life and potentially reduce medical costs.