Improving Muscle Function: Interventions to Enhance the Length and Function of Spastic Muscles

The aim of this thesis was to obtain insight into the effects of the spasticity on skeletal muscle and interventions that prevent or reduce hyper-resistance of skeletal muscle against stretch. To this end, three aims were defined: 1) To identify, evaluate and summarize the relevant literature about determinants of muscle length and length range of active force exertion, typical muscle growth, as well as stimuli to induce adaptation of these parameters; 2) to gain understanding into the effects of spasticity of calf muscles on physical performance during postnatal development in mice, and the mechanisms underlying spasticity-associated limitations in physical performance, and 3) to obtain insight in how surgical muscle lengthening and botulinum neurotoxin intramuscular injection affect muscle morphology and phenotype and how these adaptations alter long-term muscle function during development. In chapter 2 we discussed the key determinants of muscle length and length range of active force exertion, as well as typical muscle growth, and we identified potential stimuli to induce muscle length and length range adaptation in humans. Animal studies show that the effects of immobilization, strength training and stretching on morphological adaptations are strongly dependent on muscle architecture. These interventions cause different morphological adaptations in young and (young-) adult muscles-tendon complexes. The length at which muscles are mostly active and excursion over which they operate and generate force are important stimuli for longitudinal muscle growth. Furthermore, muscle activation (e.g. electrical stimulation) during passive stretching and immobilization are beneficial, as these interventions enhance addition of sarcomeres in series and limits the accumulation of connective tissue. In chapter 3 we investigated changes in muscle geometry, as well as adaptation of the number of sarcomeres in series after recovery from aponeurotomy of the proximal gastrocnemius medialis aponeurosis. We related the changes to the muscle length-force characteristics. After a 6-week recovery period, the number of sarcomeres in series of proximally and distally located muscle fibers were similar between the aponeurotomy plus recovery group and the control group. Moreover, the proximal muscle fiber mean sarcomere length was also similar between the aponeurotomy plus recovery and control group. On the other hand, the mean sarcomere length of the distal muscle fibers of aponeurotomy plus recovery group was lower than that of the control group. In addition, the proximal fibers of the aponeurotomy plus recovery group had higher mean sarcomere lengths than distal fibers, over a range of muscle lengths, which was reversed compared to the control group. This latter explains that the aponeurotomy plus recovery and control group had a similar length-force relationship. These results indicate that aponeurotomy of the proximal aponeurosis in the gastrocnemius muscle changes slightly the geometry in the long-term, such change in geometry preserves muscle function. In chapter 4 we compared the motor function, gait and physical activity of spastic mice (B6.Cg-Glrbspa/J) to that of wild-type mice during development. We assessed the morphological, histological and contractile force characteristics in the spastic soleus and gastrocnemius medialis muscles and their wild-type littermates at a juvenile and an adult age. Spastic mice showed attenuated growth, impaired motor function and low physical activity. Gait of spastic mice was characterized by a typical hopping pattern and tip-toe walking. Spastic mice showed lower muscle forces. Moreover, the muscle-tendon complex length-force relationship of adult gastrocnemius medialis was shifted towards shorter lengths compared to that of wild-type mice, likely due to an attenuated body growth. ...