Xin Is a Marker of Skeletal Muscle Damage Severity in Myopathies

Abstract

Xin is a striated muscle-specific protein that is localized to the myotendinous junction in skeletal muscle. However, in injured mouse muscle, Xin expression is up-regulated and observed throughout skeletal muscle fibers and within satellite cells. In this study, Xin was analyzed by immunofluorescent staining in skeletal muscle samples from 47 subjects with various forms of myopathy, including muscular dystrophies, inflammatory myopathies, mitochondrial/metabolic myopathy, and endocrine myopathy. Results indicate that Xin immunoreactivity is positively and significantly correlated (rs = 0.6175, P = <0.0001) with the severity of muscle damage, regardless of myopathy type. Other muscle damage measures also showed a correlation with severity [Xin actin-binding repeat-containing 2 (rs = -0.7108, P = 0.0006) and collagen (rs = 0.4683, P = 0.0783)]. However, because only Xin lacked immunoreactivity within the healthy muscle belly, any detectable immunoreactivity for Xin was indicative of muscle damage. We also investigated the expression of Xin within the skeletal muscle of healthy individuals subjected to damaging eccentric exercise. Consistent with our previously mentioned results, Xin immunoreactivity was increased 24 hours after exercise in damaged muscle fibers and within the activated muscle satellite cells. Taken together, these data demonstrate Xin as a useful biomarker of muscle damage in healthy individuals and in patients with myopathy. The strong correlation between the degree of muscle damage and Xin immunoreactivity suggests that Xin may be a suitable outcome measure to evaluate disease progression and treatment effects in clinical trials.

Aciculin interacts with filamin C and Xin and is essential for myofibril assembly, remodeling and maintenance

“…Scale bars: 5 mm. myofibrillar damage and remodeling Hawke et al, 2007;Nilsson et al, 2013). Therefore, the interaction of aciculin with these proteins in itself suggests, apart from its essential role in muscle cell attachment, an involvement in assembly, repair and remodeling of the contractile machinery.…”

“…FLNc has also been described as general marker of skeletal muscle damage in numerous neuromuscular diseases (Bönnemann et al, 2003;Sewry et al, 2002;Thompson et al, 2000). Recently, Xin has been identified as a more specific muscle-damage marker localizing in activated satellite cells (Hawke et al, 2007) and in the sarcomeric portion of muscle fibers from patients suffering from myopathies or after eccentric exercise (Nilsson et al, 2013). In healthy tissue, Xin localizes in myotendinous junctions (MTJs) in skeletal muscle and in intercalated discs in the heart (Feng et al, 2013;Otten et al, 2010;van der Ven et al, 2006;Wang et al, 1999).…”

A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency

“…Since the mutation in the Ky gene in the mouse is associated with an abnormal distribution of its binding partner FLNC and Xin, 12,13 which is a FLNC-binding partner 10 and general muscle damage marker, 14 we stained skeletal muscle sections of our patient for both proteins. Even though some parts of the sections appeared largely unaffected, in other areas inclusions containing the proteins were seen inside the fibers, with an incidence ranging from mild (fibers with mostly small inclusions) to severe (numerous fibers affected and very large inclusions) (Supplementary Figure S1).…”

Potential Biomarkers of Skeletal Muscle Damage

“…Xin, a cytoskeletal adapter protein, was recently identified as a novel biomarker of skeletal muscle damage [14]. Although undetectable within the belly of uninjured skeletal muscle, Xin expression increases with damage severity in a highly correlated manner (regardless whether the damage is a result of myopathy or eccentric exercise in healthy individuals).…”