Skeletal muscle function in patients with spinal muscular atrophy: (D)enervating studies with blocks and bikes

Fatigability has emerged as an important dimension of physical impairment reported by patients with the spinal muscular atrophy (SMA). Fatigability, for example occurring during walking, writing or combing hair, is defined as the inability to continuously perform a task on the same power output even though someone is physically capable to perform the specific task. The main objective of this thesis was to gain more insights in peripheral factors possibly underlying fatigability of skeletal muscles in patients with SMA. The development of a set of three endurance tests was the first step to facilitate studies on fatigability in ambulant as well as non-ambulant patients with SMA. During these endurance tests, we examined the presence of and the possibility to improve muscle activation. Our results indicated the availability of reserve capacity in muscles of individual patients which can be used when fatigability occurs. Furthermore, we found enhanced muscle reserve capacity in patients treated with pyridostigmine compared to a placebo. Next, we investigated skeletal muscle morphology, mitochondrial function and muscle blood supply. Quantitative MRI analyses of upper arm muscles showed to be a feasible method to map disease state of remaining muscle tissue. Muscle fat infiltration and a shift in myofiber composition explained muscle weakness in upper arms of patients with SMA. In addition, MR spectroscopy during arm cycling exercise turned out to be a promising method to map upper arm myofiber composition and muscle metabolism in patients with SMA. In conclusion, we found no evidence for the contribution of muscle metabolism and muscle blood supply as primary limiting factors to fatigability in patients with SMA.