Bone Morphogenetic Proteins and myostatin pathways: key mediator of human sarcopenia

Abstract

BackgroundSarcopenia, osteoporosis and osteoarthritis are the most frequent musculoskeletal disorders affecting older people. The main aim of this study was to test the hypothesis that the balance between BMPs and myostatin pathways regulates the age-related muscle degeneration in OP and OA patients. To this end, we investigated the relationship among the expression of BMP-2/4-7, myostatin and phosphorylated Smads1-5-8 and the muscle quality, evaluated in term of fibers atrophy and satellite cells activity.MethodsIn this retrospective study, we collected 123 biopsies of vastus lateralis: 48 biopsies from patients who underwent hip arthroplasty for subcapital fractures of the femur (OP), 55 biopsies from patients who underwent hip arthroplasty for osteoarthritis (OA) and 20 biopsies from patients who underwent hip arthroplasty for high-energy hip fractures (CTRL). Muscle biopsies were fixed in 4% paraformaldehyde and paraffin embedded. Serial sections were used for morphometrical and immunohistochemical analysis (BMP/2/4-7, myostatin, Smads1-5-8, Pax7 and myogenin). In addition, 1 mm3 of muscle tissue of each patient was embedded in epon for ultrastructural study.ResultsMorphometric data indicated an increase of the number of atrophic fibers in OP patients compare to OA. In line with these data, we found an high regenerative potential in muscle tissues of OA patients due to the significant amount of both Pax7 and myogenin positive satellite cells detected in OA group. In addition, our data showed the decrease of BMP2/4 and -7 expression in OP patients compared to both OA group and CTRL. Conversely, OP patients were characterized by high levels of myostatin expression. A different expression profile was also found for phosphorylated Smad1-5-8 between OP and OA patients. In particular, OP patients showed a low number of positive phosphorylated Smad1-5-8 nuclei.ConclusionThe identification of molecular pathways involved in the pathogenesis of sarcopenia open new prospective for the development of drugs able to prevent/treat the muscle impairment that occur in elderly. Results here reported, highlighting the role of BMPs and myostatin pathways in physio-pathogenesis of human sarcopenia, allow us to propose human recombinant BMP-2/7 and anti-myostatin antibodies as a possible therapeutic option for the sarcopenia.

Alterations in quadriceps muscle cellular and molecular properties in adults with moderate knee osteoarthritis

“…Recent work has suggested that satellite cell phenotype may dictate the regenerative potential of muscle in patients with OA 40 . Along with decreased satellite cell abundance, alterations in the phenotype of satellite cell populations may be an important contributing factor to muscle alterations in late stage OA 40,41 . Therapeutic targets that address satellite cell phenotype, abundance and ECM deposition may prove effective at increasing quadriceps strength within this cohort.…”

Current Methods for Skeletal Muscle Tissue Repair and Regeneration

“…The most promising targets include BMP and myostatin [ 105 ]. Indeed, medication with human recombinant BMP-2/7 and antimyostatin can help to reduce sarcopenic symptoms [ 106 ]. Cachexia is addressed with anamorelin, a ghrelin agonist, and selective androgen receptor modulator as well as anticytokines/myokines [ 107 ].…”

Osteocalcin Induces Proliferation via Positive Activation of the PI3K/Akt, P38 MAPK Pathways and Promotes Differentiation Through Activation of the GPRC6A-ERK1/2 Pathway in C2C12 Myoblast Cells

“…However, the precise mechanisms responsible for synchronizing bone and skeletal muscle mass remain unclear. Although basic studies have helped dissect the multiple influences of skeletal muscle on bone through cytokines such as myostatin, insulin-like growth factor 1 (IGF-1), fibroblast growth factor 2 (FGF-2), interleukin-6 (IL-6), IL-15, myostatin, osteoglycin (OGN), FAM5C, and osteoactivin [9][10][11][12][13][14], few osteokines involved in the feedback control of muscle by bone have been identified, with the exception of the osteocyte-specific Wnt family member 3a (Wnt3a), prostaglandin E2 (PGE2), osteoblast-derived IGF-1 and osteocalcin [15][16][17][18].…”