Decreased Satellite Cell Number and Function in Humans and Mice With Type 1 Diabetes Is the Result of Altered Notch Signaling

Abstract

Type 1 diabetes (T1D) negatively influences skeletal muscle health; however, its effect on muscle satellite cells (SCs) remains largely unknown. SCs from samples from rodents (Akita) and human subjects with T1D were examined to discern differences in SC density and functionality compared with samples from their respective control subjects. Examination of the Notch pathway was undertaken to investigate its role in changes to SC functionality. Compared with controls, Akita mice demonstrated increased muscle damage after eccentric exercise along with a decline in SC density and myogenic capacity. Quantification of components of the Notch signaling pathway revealed a persistent activation of Notch signaling in Akita SCs, which could be reversed with the Notch inhibitor DAPT. Similar to Akita samples, skeletal muscle from human subjects with T1D displayed a significant reduction in SC content, and the Notch ligand, DLL1, was significantly increased compared with control subjects, supporting the dysregulated Notch pathway observed in Akita muscles. These data indicate that persistent activation in Notch signaling impairs SC functionality in the T1D muscle, resulting in a decline in SC content. Given the vital role played by the SC in muscle growth and maintenance, these findings suggest that impairments in SC capacities play a primary role in the skeletal muscle myopathy that characterizes T1D.

Muscle satellite cells are functionally impaired in myasthenia gravis: consequences on muscle regeneration

“…Many diseases affecting muscle are associated with a reduction in the SC pool [26,29,73]. For example, SC reduction was found in X-linked muscular dystrophy (MDX) in mice [45] or in type 1 diabetes characterised by the alteration of Notch signalling pathway on skeletal muscle [18]. On the other hand, as observed in our study, an increase in the SC pool was described in several cases such as degenerative muscle disease [34], neuromuscular disease as "arrested development of right response" (ADR) myotonia [63], drug treatment [56], or mechanical stress [11,76].…”

Reduced Dnmt3a increases Gdf5 expression with suppressed satellite cell differentiation and impaired skeletal muscle regeneration

“…Muscle atrophy is associated with aging (sarcopenia) and chronic unloading (such as immobilization with casts), as well as nerve injury (denervation). During atrophy, the muscle regeneration capacity after injury (e.g., falling, trauma, or extreme exercise) is known to be decreased (9)(10)(11). However, the mechanism involved is largely unknown.…”

Altered satellite cell dynamics accompany skeletal muscle atrophy during chronic illness, disuse, and aging

“…D’Souza et al reported a similar decline in satellite cell activity in both rodent and clinical samples, with experiments on isolated single fibers suggesting that the decline in satellite cell function was intrinsic to satellite cells (14*). The Notch signaling pathway was also explored because it regulates satellite cell quiescence, expansion, and differentiation.…”

“…Impaired satellite cell differentiation is also observed in children with type 1 diabetes, and a mouse model of the condition (14*). D’Souza et al reported a similar decline in satellite cell activity in both rodent and clinical samples, with experiments on isolated single fibers suggesting that the decline in satellite cell function was intrinsic to satellite cells (14*).…”

“…The Notch signaling pathway was also explored because it regulates satellite cell quiescence, expansion, and differentiation. However, Notch ligand expression differed between rodent and clinical samples, clouding interpretation (14*). Future research is needed to determine the influence of Notch signaling on satellite cell dysregulation in diabetic muscle.…”