Aggresome–Autophagy Involvement in a Sarcopenic Patient with Rigid Spine Syndrome and a p.C150R Mutation in FHL1 Gene

Abstract

The four-and-half LIM domain protein 1 (FHL1) is highly expressed in skeletal and cardiac muscle. Mutations of the FHL1 gene have been associated with diverse chronic myopathies including reducing body myopathy, rigid spine syndrome (RSS), and Emery–Dreifuss muscular dystrophy. We investigated a family with a mutation (p.C150R) in the second LIM domain of FHL1. In this family, a brother and a sister were affected by RSS, and their mother had mild lower limbs weakness. The 34-year-old female had an early and progressive rigidity of the cervical spine and severe respiratory insufficiency. Muscle mass evaluated by DXA was markedly reduced, while fat mass was increased to 40%. CT scan showed an almost complete substitution of muscle by fibro-adipose tissue. Muscle biopsy showed accumulation of FHL1 throughout the cytoplasm and around myonuclei into multiprotein aggregates with aggresome/autophagy features as indicated by ubiquitin, p62, and LC3 labeling. DNA deposits, not associated with nuclear lamina components and histones, were also detected in the aggregates, suggesting nuclear degradation. Ultrastructural analysis showed the presence of dysmorphic nuclei, accumulation of tubulofilamentous and granular material, and perinuclear accumulation of autophagic vacuoles. These data point to involvement of the aggresome–autophagy pathway in the pathophysiological mechanism underlying the muscle pathology of FHL1 C150R mutation.

Melatonin as a Potential Agent in the Treatment of Sarcopenia

“…Also, some agents impair autophagy, inducing blockage, which results in vacuole accumulation [81]. Strongly supporting this hypothesis, several articles show functional defects in autophagy as a characteristic of sarcopenic muscle [7,82]; this has been occasionally accompanied by perinuclear accumulation of autophagic vacuoles [83]. …”

Mitochondrial abnormalities in the myofibrillar myopathies

“…The disorders associated with mutations in FHL1 include reducing body myopathy, X-linked dominant scapuloperoneal myopathy, X-linked myopathy with postural muscle atrophy and generalized hypertrophy, rigid spine syndrome, EmeryÀDreifuss muscular dystrophy and isolated hypertrophic cardiomyopathy [38]. Rubbed out fibres [39][40][41][42][43][44], ragged red or COX-negative fibres and altered mitochondrial morphology have been described in muscle from patients manifesting with the different clinical phenotypes [43,45,46].…”

Dying myofibers in elderly mouse skeletal muscles are characterized by the appearance of dystrophin-encircled vacuoles

“…(2) DAPI stained nuclei were often found in DEVILs, but never in ice crystal artifacts. (3) DEVILated myofibers were exclusively found within four fiber diameters of the superficial layer, and aggregated near connective tissue or ghosted myofibers, possibly the remnants of dead myofibers (Sabatelli et al 2014;Wheeler 1982). By contrast, ice crystal artifacts were widespread and found throughout the affected regions of muscles (Fig.…”

“…Such observations may suggest that the pathogenesis of DEVILs may only be partly underpinned by autophagic dysfunction, and that other factors such as dysfunction among the non-contractile cells and extracellular matrix may play a role in the emergence of DEVILated myofibers (Zanoteli et al 2010). It is also conceivable that connective tissue infiltration of DEVILated myofibers demarcates a later stage in their degeneration and is often seen in late-stage autophagic myopathies (Sabatelli et al 2014).…”