Abstract
Skeletal muscle regeneration is ensured by satellite cells (SC), which upon activation undergo self-renewal and myogenesis. The correct sequence of healing events may be offset by inflammatory and/or fibrotic factors able to promote fibrosis and consequent muscle wasting. Angiotensin-II (Ang) is an effector peptide of the renin angiotensin system (RAS), of which the direct role in human SCs (hSCs) is still controversial. Based on the hypertrophic and fibrogenic effects of Ang via transient receptor potential canonical (TRPC) channels in cardiac and renal tissues, we hypothesized a similar axis in hSCs. Toward this aim, we demonstrated that hSCs respond to acute Ang stimulation, dose-dependently enhancing p-mTOR, p-AKT, p-ERK1/2 and p-P38. Additionally, sub-acute Ang conditioning increased cell size and promoted trans-differentiation into myofibroblasts. To provide a mechanistic hypothesis on TRPC channel involvement in the processes, we proved that TRPC channels mediate a basal calcium entry into hSCs that is stimulated by acute Ang and strongly amplified by sub-chronic Ang conditioning. Altogether, these findings demonstrate that Ang induces a fate shift of hSCs into myofibroblasts and provide a basis to support a benefit of RAS and TRPC channel blockade to oppose muscle fibrosis.
Highlights
Healthy skeletal muscle has a powerful regenerative potential that enables physiological growth and efficient repair following insults
Cells stained positive for myogenic factor 5 (MYF5) and myogenic factor 3 (MYOD), two transcription factors of myogenic lineage [32]; at the same time, they were negative for the transcription factor myogenin and the contractile protein myosin heavy chain (MHC), indicating the absence of myogenic differentiation
Despite Ang is recognized as a potent fibrogenic factor in the muscle [2], little information is available on human satellite cells (SCs) (hSCs) as cell mediators of fibrosis [33]
Summary
Healthy skeletal muscle has a powerful regenerative potential that enables physiological growth and efficient repair following insults. Regardless of the prominent effects, evidence in cardiovascular patients indicates that long-term therapies with angiotensin-converting enzyme inhibitors (ACEIs) or Ang type-1 (AT1) receptor antagonists (ARBs) [7,8] slow down the progressive decline of muscle mass and contractile performance, often associated with cardiac and renal hypertrophy and fibrosis [9,10,11,12,13,14,15,16,17] It is not clear whether ACEIs or ARBs ameliorate muscle wasting through the benefits exerted at cardiac and renal levels or whether they directly enhance muscle regenerative capacity and/or its resistance to injuries. Since Ca2+ dynamics regulates skeletal muscle development, homeostasis, and regeneration [29,30], we hypothesized a possible role of Ang-TRPC channel axis on hSC fate determination toward non-myogenic lineage To test this hypothesis, in this study, we provided evidence that Ang promotes hypertrophy and myofibroblast trans-differentiation of hSCs and that this fate decision is associated to Ca2+ entry via activation of TRPC channels. To elucidate the mechanisms and provide a basis to support clinical benefits of RAS blockade in muscle fibrosis and wasting, the effects of Ang were evaluated in the presence of irbesartan (Irb), an AT1 receptor antagonist
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