Dr. Susan A. Bloomfield’s research seeks to define an optimal exercise regimen that will mitigate bone loss when combined with the administration of an appropriate drug agent. To enhance muscle and bone recovery, Bloomfield’s animal study will test the hypothesis that astronaut time spent exercising to reduce bone loss can be decreased if combined with an appropriate pharmacological agent. She will first compare two distinct exercise types, both mimicking weight training, then administer the pharmalogical agent in combination with the most successful exercise mode, and then systematically determine what reduction in exercise time results in the most benefit to bone and muscle. Her results can then be translated to flight-based study.
Overview
Increasing the Efficiency of Exercise Countermeasures for Bone Loss
Principal Investigator:
Susan A. Bloomfield, Ph.D.
Organization:
Texas A&M University
Technical Summary
The over-arching goal of this project was to test the hypothesis that astronaut exercise time devoted to mitigation of bone loss can be reduced if combined with an anti-resorptive pharmacological agent. Skeletal muscle mass, function and anabolic markers were also assessed to assure that any reductions in exercise time did not sacrifice benefits to muscle.
Original Aims
- Test two different modes of resistance training (electrically stimulated muscle contractions versus voluntary resistance exercise) for their effects on mitigating bone and muscle decrements during 28 days of hindlimb unloading (HU) in adult rats;
- To test different doses of alendronate during 28 days HU for maximal efficacy in suppressing bone resorption; and then
- To combine alendronate with that training paradigm judged most successful to test for additive or synergistic effects.
Year 1 of this project was largely devoted to the adaptation of a flywheel device for voluntary resistance training in HU rats and to modifications of our existing muscle stimulation system, which allows for precisely controlled (but involuntary, therefore less physiological) muscle contraction regimens of the rats lower leg. This latter system became the training paradigm of choice for the remainder of the project. In Year 3, a revision of the simulated resistance training (sRT) protocol was completed in hopes of maintaining the positive impact on bone mass and strength and providing some mitigation of the loss of skeletal muscle function and mass. The primary changes in the training paradigm were:
- Decreasing the intensity of muscle contractions;
- Changing the range of motion allowed at the ankle during lower leg contractions, to achieve a greater stretch on the posterior crural muscle group; and
- Adding one second of isometric muscle contraction to the one second of eccentric contraction.
In our final year, we completed a record number of experiments. A dose finding experiment with three doses of alendronate was completed in order to define the minimally efficacious dose of alendronate, which turned out to be 0.01 or 0.03 mg/kg (delivered three days per week), depending on which variable of bone mass or geometry was examined. A small n trial testing the efficacy of sRT performed at a lower intensity (75 versus 100 percent peak isometric torque) verified that this reduced intensity produced more promising results for skeletal muscle while retaining its prevention of disuse-induced bone loss.
Our final animal experiments tested the separate and combined effects of reduced-volume sRT reduced intensity along with a reduced frequency (two days per week) with the lowest dose of alendronate exhibiting any positive mitigation of bone loss (0.01 mg/kg BW). The pQCT data indicate that sRT effectively mitigated the losses of bone mineral content/density, especially in the cancellous compartment of the proximal tibia which is that bone compartment most affected by the unloading of tail suspension. In fact, for some variables, HU rats on sRT alone experienced a gain in bone during the unloading period. This was remarkable, given the reduced intensity and frequency of training used in this last protocol. Salutary effects were also observed at the mid-shaft tibia with sRT. New to this particular sRT stimulation protocol, we demonstrated effective maintenance of lower leg muscle strength: peak isometric torque of the lower leg muscles was effectively maintained in rats subjected to the sRT versus the 10 percent decrease observed in rats on HU alone.
Alendronate treatments during 28 days HU were effective in mitigating bone loss only at the proximal tibia but appeared to have no effect on preventing the commonly observed disuse-induced suppression of periosteal expansion of mid-shaft tibia. Combining alendronate with sRT did not result in additional bone benefits beyond those observed with the training alone. The unexpected success of this reduced-volume sRT in preventing HU-induced bone loss, and on occasion stimulating absolute gains in bone mass, prevents us from answering one of our central hypotheses that a marginally effective exercise countermeasure, combined with anti-resorptive effects of alenronate, would effectively mitigate bone loss. Hence, our preliminary conclusion is that the mechanical (and/or metabolic) stimulation of bone with high-force muscle contractions of an isometric/eccentric nature, even if performed only twice per week, appears to be an effective countermeasure for bone loss with unloading and can maintain ankle plantarflexor muscle strength if not muscle mass. This provides an important proof of concept: if resistance training includes muscle contractions at high enough intensities, with isometric and eccentric components, significant mitigation or prevention of bone loss and of reduced muscle strength is achievable. We expect that assays in progress (skeletal muscle anabolic markers, detailed histomorphometric studies of cancellous bone) will not modify this conclusion, but will provide important tissue- or cell-level mechanisms for these effects.
Earth Applications
Our multiple trials testing the bone and muscle response to resistance training applied as a countermeasure during a period of simulated microgravity provide an important proof of concept: if resistance training performed during a period of prolonged non-weight bearing includes isometric and eccentric muscle contractions at high enough intensities, significant mitigation of bone loss and reduced muscle strength are achievable. Remarkably, we demonstrated that 40 seconds worth of muscle contraction, performed only twice per week, effectively prevented bone loss at the proximal tibia (a disuse-sensitive site) and maintained peak strength of the lower limb muscles. We also confirmed that the anti-resorptive agent alendronate, given at one-to-three times the dose level effective against bone loss due to estrogen deficiency, can effectively mitigate losses of bone during disuse. However, alendronates salutory effect appears to be limited to metaphyseal bone (e.g. proximal tibia), whereas our resistance training paradigm had beneficial effects at that site and on mid-shaft bone as well. One clear implication of these findings for the public and for healthcare professionals is that small volumes of isometric plus eccentric-based strength training may be effective in minimizing loss of bone mass and skeletal integrity during prolonged periods of disuse (e.g., prolonged bed rest). This has important implications for rehabilitation specialists, physical therapists and clinicians treating bedridden patients.
This project's funding ended in 2008