Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle.

Aging skeletal muscles suffer a steady decline in mass and functional performance, and compromised muscle integrity as fibrotic invasions replace contractile tissue, accompanied by a characteristic loss in the fastest, most powerful muscle fibers. The same programmed deficits in muscle structure and function are found in numerous neurodegenerative syndromes and disease-related cachexia. We have generated a model of persistent, functional myocyte hypertrophy using a tissue-restricted transgene encoding a locally acting isoform of insulin-like growth factor-1 that is expressed in skeletal muscle (mIgf-1). Transgenic embryos developed normally, and postnatal increases in muscle mass and strength were not accompanied by the additional pathological changes seen in other Igf-1 transgenic models. Expression of GATA-2, a transcription factor normally undetected in skeletal muscle, marked hypertrophic myocytes that escaped age-related muscle atrophy and retained the proliferative response to muscle injury characteristic of younger animals. The preservation of muscle architecture and age-independent regenerative capacity through localized mIgf-1 transgene expression suggests clinical strategies for the treatment of age or disease-related muscle frailty.

Stem cell-mediated muscle regeneration and repair in aging and neuromuscular diseases.

One of the most exciting aspirations of current medical science is the regeneration of damaged body parts. The capacity of adult tissues to regenerate in response to injury stimuli represents an important homeostatic process that until recently was thought to be limited in mammals to tissues with high turnover such as blood and skin. However, it is now generally accepted that each tissue type, even those considered post-mitotic, such as nerve or muscle, contains a reserve of undifferentiated progenitor cells, loosely termed stem cells, participating in tissue regeneration and repair. Skeletal muscle regeneration is a coordinate process in which several factors are sequentially activated to maintain and preserve muscle structure and function upon injury stimuli. In this review, we will discuss the role of stem cells in muscle regeneration and repair and the critical role of specific factors, such as IGF-1, vasopressin and TNF-alpha, in the modulation of the myogenic program and in the regulation of muscle regeneration and homeostasis.

Detection of 1cen--1q12 lesions in different phases of the cell cycle: dual colour FISH analysis of peripheral lymphocytes from subjects with occupational exposure to petroleum fuels.

Dual colour FISH was used to assess the genotoxic effects of exposure to petroleum fuels and low benzene levels in peripheral lymphocytes of 12 gasoline station attendants. Labelled DNA probes were used for hybridization of the 1cen and 1q12 contiguous regions of chromosome 1, allowing simultaneous detection of hyperploidy and breakages in both interphase and metaphase cells. The analysis of interphase cells (either unstimulated or mitogen stimulated) showed a prevalence of cells with signal separation in exposed workers compared to matched controls. This difference was highly significant (P < 0.001) in stimulated lymphocytes (9.9 +/- 3.3 and 6.5 +/- 1.5 per thousand in exposed and controls, respectively). Far lower incidences of breaks, with no relation to chemical exposure, were detected in metaphase cells (0.3 +/- 0.8 versus 0.7 +/- 1.0 per thousand, respectively). The analysis of post-mitotic, cytokinesis-blocked cells again showed a relatively high incidence of nuclei with displacement of fluorescent signals (7.2 +/- 2.4 and 5.6 +/- 1.7 per thousand, respectively), suggesting that chromatin decondensation, rather than alteration of DNA strand integrity, led to signal separation in interphase nuclei. Even though the mechanism leading to the separation of alpha and classical satellites in interphase nuclei has not been elucidated, the significant association between cytogenetic findings and intensity of benzene exposure (as shown by the analysis of internal exposure biomarkers) suggests that signal displacement in 1cen-1q12 may be a marker of chemical exposure.