Degradation of myofibrillar proteins and inadequate antioxidants in selective muscle wasting of limb girdle muscular dystrophy

Abstract

Introduction: An unexplained feature of inherited muscular dystrophies is the wasting of selective muscle. Transcriptional signatures that differ between muscles may contribute to selective muscle wasting of muscular dystrophies. Biochemical signaling pathways involved in selective wasting have not been studied. Case Report: This study examined signaling mechanisms that stimulate protein degradation, which may govern selective muscle wasting, in a patient with Miyoshi myopathy. Oxidative stress, nitric oxide signaling and protein degradation through the ubiquitin proteasome pathway were studied in relatively spared hamstring and wasted gastrocnemius muscle of the patient and in control muscle. Oxidative stress occurred in spared and wasted Miyoshi myopathic muscle. A strong anti-oxidant response was observed in spared muscle. Tyrosine nitration of 56kDa protein(s) was 2.3 and 5 fold higher in spared and wasted muscles respectively compared to normal. Nitrocysteinylated proteins were comparable between spared hamstring and normal muscle but reduced 35% in gastrocnemius muscle compared to normal. Ubiquitinylated proteins were increased 2.6 fold in the hamstring muscle and 1.6 fold in the gastrocnemius muscle compared to normal. The protein content of the hamstring and gastrocnemius muscles was reduced 43% and 37% respectively compared to normal. Myosin heavy chain and actin levels were normal in hamstring muscle but reduced nearly four fold in gastrocnemius muscle compared to normal. Conclusion: Oxidative and nitrosative stress and loss of actin and myosin were associated with selective muscle wasting of Miyoshi myopathy. A strong anti-oxidant response that protects myofibrillar proteins against degradation may spare muscle in Miyoshi myopathy.