Are mechanically sensitive regulators involved in the function and (patho)physiology of cerebral palsy-related contractures?

Abstract

Skeletal muscle tissue is mechanosensitive, as it is able to sense mechanical impacts and to translate these into biochemical signals making the tissue adapt. Among its mechanosensitive nature, skeletal muscle tissue is the largest metabolic organ of the human body. Disturbances in skeletal muscle mechanosensing and metabolism cause and contribute to many diseases, i.e. muscular dystrophies/myopathies, cardiovascular diseases, COPD or diabetes mellitus type 2. A less commonly focused muscle-related disorder is clinically known as muscle contractures that derive from cerebral palsy (CP) conditions in young and adults. Muscle contractures are characterized by gradually increasing passive muscle stiffness resulting in complete fixation of joints. Different mechanisms have been identified in CP-related contractures, i.e. altered calcium handling, altered metabolism or altered titin regulation. The muscle-related extracellular matrix (ECM), specifically collagens, plays a role in CP-related contractures. Herein, we focus on mechanically sensitive complexes, known as costameres (Cstms), and discuss their potential role in CP-related contractures. We extend our discussion to the ECM due to the limited knowledge of its role in CP-related contractures. The aims of this review are (1) to summarize CP-related contracture mechanisms, (2) to raise novel hypotheses on the genesis of contractures with a focus on Cstms, and (3) to stimulate novel approaches to study CP-related contractures.

Evidence for skeletal muscle fiber type-specific expressions of mechanosensors

“…Cstms are specialized structures for mechanosensing and mechanical signal ampliication of striated muscle ibers [34]. Many Cstms components are involved in the control of physiological SkM development and iber integrity [6]. In particular, ILK [8,35], ITGA7 [10], ITGB1D [36, 37], FERMT2 [13] or TLN [11] is indispensable for SkM physiology and integrity.…”

“…However, it remains unknown if this Cstms-dependent mechanical impact conversion operates iber type-speciically. Cstms are multiprotein complexes that localize beneath the sarcolemma and physically link to transmembrane heterodimeric integrin [6]. Therefore, Cstms function as 'hubs' to convert mechanical impacts reaching individual SkM ibers into biological signals to mediate SkM iber adaptations to these impacts [5].…”

“…The knowledge about iber type-speciic Cstms will enhance our comprehension of processes governing diferential adaptations between type 1 and type 2 ibers. The composition of Cstms in SkM ibers appears to be diverse [6] and their spatiotemporal assembly determines downstream adaptations in the respective SkM ibers [7,8]. The integrin receptor complex (IRC) of Cstms deines a mechano-sensitive unit composed of integrins [mainly α5 (ITGA5), α7 (ITGA7), and β1D (ITGB1D) subunits] and the integrin-linked kinase (ILK)-pinch-parvin (IPP) complex [7].…”

Understanding skeletal muscle in cerebral palsy: a path to personalized medicine?

“…This decrease in sarcomerogenesis, coupled with more normal bone growth, provides one plausible reason as to the relative shortening of CP muscle over time. [13][14][15][16][17][18] Satellite cells, which are required for myofiber growth and regeneration in skeletal muscle, 19 are a recent area of interest with respect to disordered muscle growth in CP. These stem cells are reduced by up to 60% in children with CP versus typically developing children.…”

“…The reason for the decreased size of muscle in CP has been purported to be secondary to disordered growth, the mechanisms of which are not yet understood. This decrease in sarcomerogenesis, coupled with more normal bone growth, provides one plausible reason as to the relative shortening of CP muscle over time 13–18 …”