A mutation in alpha-tropomyosinslow affects muscle strength, maturation and hypertrophy in a mouse model for nemaline myopathy

Abstract

Nemaline myopathy is a hereditary disease of skeletal muscle defined by a distinct pathology of electron-dense accumulations within the sarcomeric units called rods, muscle weakness and, in most cases, a slow oxidative (type 1) fiber predominance. We generated a transgenic mouse model to study this disorder by expressing an autosomal dominant mutant of alpha-tropomyosin(slow) previously identified in a human cohort. Rods were found in all muscles, but to varying extents which did not correlate with the amount of mutant protein present. In addition, a pathological feature not commonly associated with this disorder, cytoplasmic bodies, was found in the mouse and subsequently identified in human samples. Muscle weakness is a major feature of this disease and was examined with respect to fiber composition, degree of rod-containing fibers, fiber mechanics and fiber diameter. Hypertrophy of fast, glycolytic (type 2B) fibers was apparent at 2 months of age. Muscle weakness was apparent in mice at 5-6 months of age, mimicking the late onset observed in humans with this mutation. The late onset did not correlate with observed changes in fiber type and rod pathology. Rather, the onset of muscle weakness correlates with an age-related decrease in fiber diameter and suggests that early onset is prevented by hypertrophy of fast, glycolytic fibers. We suggest that the clinical phenotype is precipitated by a failure of the hypertrophy to persist and therefore compensate for muscle weakness.

Loss of Par-1a/MARK3/C-TAK1 Kinase Leads to Reduced Adiposity, Resistance to Hepatic Steatosis, and Defective Gluconeogenesis

“…Thus, we conclude that the observed decrease in the adipose tissue of Par-1a null mice is due to decreases in total adipocyte cell number, not cell size, findings similar to those made for Par-1b null mice (43). We also determined the weight of muscle samples (tibialis anterior, gastrocnemius, plantaris, diaphragm, and extensor digitorum longus) typically used for the assessment of myogenic phenotypes and fiber type composition (22,84), which, under HFD conditions, showed significantly decreased weights (WT, P ϭ 3.7e Ϫ6 ; Par-1 Ϫ/Ϫ , P ϭ 0.006; both t tests) (Fig. 4A, column e).…”

Ca 2+ dysregulation in Ryr1 I4895T/wt mice causes congenital myopathy with progressive formation of minicores, cores, and nemaline rods

“…S3), are diagnostic of core myopathy (1,2,9). In contrast to humans, type 1 fiber predominance is not a feature in the IT/ϩ mouse model, nor is it in the ␣-tropomyosin related nemaline myopathy mouse model (25). A possible explanation for this discrepancy might lie in murine skeletal muscle physiology, which is strongly dependent on fast-twitch muscle activity (26).…”

KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy

“…Deletion of Acta1 and Neb in mice, the 2 most frequently implicated proteins in NM (1), results in neonatal lethality and muscle dysfunction, but classical nemaline bodies are not reported (36)(37)(38)41). Currently, nemaline bodies are only reproduced in mouse models of NM in which mutant protein is overexpressed, suggesting that mutant proteins are required for protein aggregation to form rods (42)(43)(44). A previous study noted that the presence of nemaline bodies does not correlate with the severity of the disease (2).…”