Biomedical subjects

Grace K Pavlath

Publications and source records attributed to Grace K Pavlath.

23 records · Page 2Linked to original sources

PubMed2002

Regulation of class I MHC expression in skeletal muscle: deleterious effect of aberrant expression on myogenesis.

Aberrant expression of class I major histocompatibility complex (MHC) occurs on myofibers in inflammatory myopathies. The mechanisms responsible for such expression are unknown. Here we show that class I MHC expression is developmentally regulated during muscle regeneration with significant levels only in myoblasts. Injection of gamma-IFN plasmid leads to muscle inflammation, induction of class I MHC in regenerating, but not mature myofibers, and attenuation of regeneration. Gene transfer of class I MHC in vivo and in vitro also attenuates muscle differentiation. Thus, cytokines may contribute to the pathogenesis of inflammatory myopathies by upregulating class I MHC and leading to deleterious effects on muscle repair.

Animals↗

PubMed2002

Multiple roles of calcineurin in skeletal muscle growth.

Adequate muscle mass and function are critical for human health. Several types of skeletal muscle growth, including regeneration and growth after atrophy, can occur in the rehabilitative period after orthopaedic surgery. The molecular pathways regulating growth of skeletal muscle in adults are understood poorly. The role of calcineurin in regulating regeneration and growth of atrophied skeletal muscle is discussed. Understanding the molecular and cellular pathways that regulate such muscle growth may lead to the development of strategies to enhance muscle growth, thereby facilitating rehabilitation after orthopaedic surgery.

Animals↗

PubMed2002

Calcineurin differentially regulates maintenance and growth of phenotypically distinct muscles.

Adequate muscle mass is critical for human health. The molecular pathways regulating maintenance and growth of adult skeletal muscle are little understood. Calcineurin (CN) is implicated as a key signaling molecule in hypertrophy. Whether CN is involved in all forms of muscle growth or in different muscles is unknown. Here, we examine the role of CN in regulating maintenance of muscle size and growth of atrophied muscle in the soleus (slow) and plantaris (fast). The CN inhibitor cyclosporin A (CsA) differentially affects muscle growth and maintenance depending on muscle phenotype. The plantaris is more severely affected by CsA than the soleus in both growth conditions. One-week vs. 2-wk CsA treatment suggests that both CN-dependent and CN-independent growth occur in the atrophied soleus, whereas plantaris growth appears to be totally CN dependent. Our results suggest that CN regulates multiple types of muscle growth, depending both on muscle phenotype and stage of myofiber growth. Differential expression of components of the CN pathway occurs and may contribute to the differences between muscles.

Animals↗

PubMed2002

Cell-type-dependent up-regulation of in vitro mineralization after overexpression of the osteoblast-specific transcription factor Runx2/Cbfal.

Functional expression of the transcriptional activator Runx2/Cbfal is essential for osteoblastic differentiation and bone formation and maintenance. Forced expression of Runx2 in nonosteoblastic cells induces expression of osteoblast-specific genes, but the effects of Runx2 overexpression on in vitro matrix mineralization have not been determined. To examine whether exogenous Runx2 expression is sufficient to direct in vitro mineralization, we investigated sustained expression of Runx2 in nonosteoblastic and osteoblast-like cell lines using retroviral gene delivery. As expected, forced expression of Runx2 induced several osteoblast-specific genes in NIH3T3 and C3H10T1/2 fibroblasts and up-regulated expression in MC3T3-E1 immature osteoblast-like cells. However, Runx2 expression enhanced matrix mineralization in a cell-type-dependent manner. NIH3T3 and IMR-90 fibroblasts overexpressing Runx2 did not produce a mineralized matrix, indicating that forced expression of Runx2 in these nonosteogenic cell lines is not sufficient to direct in vitro mineralization. Consistent with the pluripotent nature of the cell line, a fraction (25%) of Runx2-expressing C3H10T1/2 fibroblast cultures produced mineralized nodules in a viral supernatant-dependent manner. Notably, bone sialoprotein (BSP) gene expression was detected at significantly higher levels in mineralizing Runx2-infected C3H10T1/2 cells compared with Runx2-expressing cultures which did not mineralize. Treatment of Runx2-infected C3H10T1/2 cultures with dexamethasone enhanced osteoblastic phenotype expression, inducing low levels of mineralization independent of viral supernatant. Finally, Runx2 overexpression in immature osteoblast-like MC3T3-E1 cells resulted in acceleration and robust up-regulation of matrix mineralization compared with controls. These results suggest that, although functional Runx2 is essential to multiple osteoblast-specific activities, in vitro matrix mineralization requires additional tissue-specific cofactors, which supplement Runx2 activity.

3T3 Cells↗

PubMedDate not supplied

Cell fusion in skeletal muscle--central role of NFATC2 in regulating muscle cell size.

Skeletal muscle formation and growth require the fusion of myoblasts to form multinucleated myofibers or myotubes. Studies of the calcium activated transcription factor NFATC2 demonstrate that cell fusion during myogenesis occurs in two distinctly regulated phases. NFATC2 controls myoblast fusion after the initial formation of a myotube and is necessary for further cell growth. Recently we have shown that following myotube formation, myotubes recruit myoblast fusion by secretion of IL-4 and prostaglandin F2alpha. Molecules that control muscle cell fusion are of great interest from a therapeutic standpoint to enhance growth of muscle after injury or to alleviate the loss of muscle mass found in disease or aging.

Animals↗