Somatic cell fusion is an essential component of skeletal muscle development and growth and repair from injury. Additional cell types such as trophoblasts and osteoclasts also require somatic cell fusion events to perform their physiological functions. Currently we have rudimentary knowledge on molecular mechanisms regulating somatic cell fusion events in mammals. We therefore investigated during in vitro murine myogenesis a mammalian homolog, Kirrel, of the Drosophila Melanogaster genes Roughest (Rst) and Kin of Irre (Kirre) which regulate somatic muscle cell fusion during embryonic development. Our results demonstrate the presence of a novel murine Kirrel isoform containing a truncated cytoplasmic domain which we term Kirrel B. Protein expression levels of Kirrel B are inverse to the occurrence of cell fusion events during in vitro myogenesis which is in stark contrast to the expression profile of Rst and Kirre during myogenesis in Drosophila. Furthermore, chemical inhibition of cell fusion confirmed the inverse expression pattern of Kirrel B protein levels in relation to cell fusion events. The discovery of a novel Kirrel B protein isoform during myogenesis highlights the need for more thorough investigation of the similarities and potential differences between fly and mammals with regards to the muscle cell fusion process.

Maladaptive endoplasmic reticulum (ER) stress is associated with modified reactive oxygen species (ROS) generation, altered mitochondrial bioenergetics, and oxidative damage; and is postulated as a potential mechanism involved in the underlying muscle weakness experienced by patients with myositis, an acquired autoimmune neuromuscular disease. In this study, we investigate the impact of ROS generation in an in vitro model of ER stress in skeletal muscle, using the ER stress inducer tunicamycin (24 hours) in presence or absence of a superoxide dismutase/catalase mimetic Eukarion (EUK)-134. ER stress activation, ROS generation, mitochondrial function, biogenesis, morphology and dynamics (fusion/fission) were examined. Tunicamycin induced maladaptive ER stress, validated by stimulation of GRP94, GRP78, CHOP, XBP-1, ERDJ4, and GADD34, which were mostly mitigated by EUK-134 at transcriptional level. ER stress triggered mitochondrial unfolded protein response and promoted mitochondrial dysfunction, described by substantial loss of mitochondrial membrane potential, as well as reduction of respiratory control ratio, reserve capacity, phosphorylating respiration, and coupling efficiency, which was ameliorated by EUK-134. ROS-mediated biogenesis and fusion of mitochondria was evident in presence of tunicamycin, which however, had high propensity of fragmentation, accompanied by upregulated mRNA levels of fission-related markers. Increased cellular ROS generation oxidative stress was observed in response to ER stress that was ameliorated in the presence of EUK-134, even though no changes in mitochondrial superoxide were noticeable. These findings suggest that targeting ROS generation using the superoxide dismutase/catalase mimetic EUK-134 can amend aspects of ER stress-induced changes in mitochondrial dynamics and function. Overall, this study suggests that in instances of chronic ER stress, such as in myositis, quenching ROS generation may be a promising therapy for muscle weakness and dysfunction.

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Introduction: Sarcopenia is associated with morbidity and mortality. Cellular pathways involved in the regulation of growth and atrophy affect myofibre size and subsequently, muscle strength. The objective of this study was to investigate whether skeletal muscle gene expression was associated with altered lean mass and grip strength in community-dwelling older men.Methods: 99 men (mean age 72 years) consented for detailed characterisation of muscle mass and strength as well as a muscle biopsy of the vastus lateralis. Tissue suitable for molecular analysis was available from 88 participants. PCR arrays on muscle tissue were used to determine the expression of 44 genes implicated in the cellular regulation of skeletal muscle. The relationships between gene expression, lean mass and grip strength were described.

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