The primary objective of this renewal proposal is to investigate the role of force and length changes in maintaining the functional, structural and metabolic integrity of skeletal muscles that have been subjected to long- term periods of inactivity. A second objective is to initiate experiments to parcel out the contribution of neural (neurotrophic), mechanical (tension) and humoral (thyroid) factors in maintaining muscle properties. Adaptation will be studied from the whole muscle to the molecular (the myosin molecule in particular) level in a homogeneously slow extensor muscle, the cat soleus, which has been shown to be affected dramatically by decreased use. Inactivity in the hindlimb musculature of adult females cats will be produced by spinal cord isolation (SI), i.e., spinal cord transection at T12-T13 and L7-S1 and bilateral dorsal rhizotomy between the two transection sites. Bipolar intramuscular recording electrodes will be implanted bilaterally in the lateral gastrocnemius (LG) and tibialis anterior muscles to monitor EMG activity throughout the experimental period. In some SI cats, stimulating electrodes will be implanted bilaterally near the lateral gastrocnemius-soleus nerve within the LG and will be used to periodically stimulate the soleus over a 4 month period. For 30 min/day, 5 days/week, these cats will be placed in a harness, the legs secured to a pedal mounted on an oscillating arm and the soleus stimulated isometrically or during the shortening or lengthening phase of an oscillating cycle that will produce a range of excursions in the soleus similar to that observed during a step cycle on a treadmill. The legs of another group of cats will be manipulated passively through the same cycle. At various times during the experimental period, tendon force transducers will be implanted acutely on the distal tendon of the soleus muscles to quantify the forces imposed on the muscle during the stimulation protocol. After the most effective stimulation paradigm is characterized, a second group of cats will be made either hyper- or hypothyroid and subjected to this stimulation paradigm. In situ whole muscle and motor units will be compared across groups. The myosin molecule will be thoroughly characterized biochemically and histochemically and these data correlated with the functional properties. These studies should provide valuable insight into the molecular mechanisms involved in the adaptation of myosin gene expression associated with carefully programmed amounts and types of mechanical loading. In addition, the results should provide data relative to the most appropriate type of manipulation (passive vs active, isometric vis isotonic, eccentric vs concentric, etc.) to use as a preventive and/or rehabilitative aid to patients with muscular and neuromuscular maladies.
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