Abnormalities in Early Markers of Muscle Involvement Support a Delay in Myogenesis in Spinal Muscular Atrophy

Abstract

Spinal muscular atrophy (SMA) is characterized by loss of motor neurons in the spinal cord that results in muscle denervation and profound weakness in affected patients. We sought evidence for primary muscle involvement in the disease during human development by analyzing the expression of several muscle cytoskeletal components (i.e. slow, fast, and developmental myosin, desmin, and vimentin) in fetal or postnatal skeletal muscle samples from 5 SMA cases and 6 controls. At 14 weeks' gestation, SMA samples had higher percentages of myotubes expressing fast myosin and lower percentages of myotubes expressing slow myosin versus control samples. Desmin and vimentin were highly expressed at prenatal stages without notable differences between control and SMA samples, although both proteins showed persistent immunostaining in atrophic fibers in postnatal SMA samples. We also studied the expression of Pax7-positive nuclei as a marker of satellite cells and found no differences between control and SMA prenatal samples. There was, however, a significant increase in satellite cells in postnatal atrophic SMA fibers, suggesting an abnormal myogenic process. Together, these results support the hypothesis of a delay in muscle maturation as one of the primary pathologic components of SMA. Furthermore, myosins and Pax7 may be useful research markers of muscle involvement in this disease.

Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy

“…Observations by different authors suggested that the myogenic program is deregulated in SMA mice models, 34 human myoblasts, 35 and postnatal muscle samples 18 from patients with SMA. We quantified expression levels of 3 myogenic regulatory factors, namely, myoblast determination 1 (MYOD), myogenin (MYOG), and the muscle-specific myogenic factor 5 (MYF5) in SMA-I samples (n = 3) and age-matched controls (n = 4).…”

“…38 Recent investigations have demonstrated that SMN has a role in myogenesis and that normal muscle differentiation requires adequate levels of SMN 34,35 ; these considerations support the hypothesis that a delay in muscle maturation is one of the primary pathologic components of SMA. 18 …”

“…17 In addition, a few studies hypothesize a delay in myogenesis showing constitutive abnormalities in muscle cultures from patients with SMA and an altered expression of several muscle components, including developmental myosins, desmin, and vimentin. 18 …”

209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7–9 November 2014, Heemskerk, The Netherlands

“…Also, immature appearing proximal axons and dorsal root ganglia have been identified. Collectively, this suggests an element of developmental arrest in SMN deficient nerve and muscle and suggests that SMA is not purely a progressive neurodegenerative process [13]. Polyneuronal innervation of muscle in the early post-natal mouse differs from that in the human where one axon probably innervates one muscle fibre at birth.…”

Regulation of Satellite Cell Function in Sarcopenia

“…For example, acute satellite cell proliferation has been reported in response to spinal muscular atrophy-induced muscle denervation (Martinez-Hernandez et al, 2014) presumably as an attempt to increase the nuclear population for elevating transcriptional signaling, yet, the atrophy signaling predominates the muscle, and the net result is that denervated muscles become smaller, even with an acute increase in satellite cells. Thus, effective strategies to combat sarcopenia and accelerated muscle loss in aging should evaluate the effects of interventions on both proliferation and differentiation of satellite cells and their daughter cells.…”