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Counteracting muscle wasting in aging and neuromuscular diseases: the critical role of IGF-1.

Scicchitano BM, Rizzuto E, MusarĂ² A - Aging (Albany NY) (2009)

Bottom Line: Most muscle pathologies are characterized by the progressive loss of muscle tissue due to chronic degeneration combined with the inability of regeneration machinery to replace the damaged muscle.Among them, insulin-like growth factor-1 (IGF-1) has been implicated in the control of skeletal muscle growth, differentiation, survival, and regeneration and has been considered a promising therapeutic agent in staving off the advance of muscle weakness.Here we review the molecular basis of muscle wasting associated with diseases, such as sarcopenia, muscular dystrophy and Amyotrophic Lateral Sclerosis, and discuss the potential therapeutic role of local IGF-1 isoforms in muscle aging and diseases.

View Article: PubMed Central - PubMed

Affiliation: Institute Pasteur Cenci-Bolognetti, Department of Histology and Medical Embryology, IIM, Sapienza University of Rome, Rome 00161, Italy.

ABSTRACT
Most muscle pathologies are characterized by the progressive loss of muscle tissue due to chronic degeneration combined with the inability of regeneration machinery to replace the damaged muscle. These pathological changes, known as muscle wasting, can be attributed to the activation of several proteolytic systems, such as calpain, ubiquitin-proteasome and caspases, and to the alteration in muscle growth factors. Among them, insulin-like growth factor-1 (IGF-1) has been implicated in the control of skeletal muscle growth, differentiation, survival, and regeneration and has been considered a promising therapeutic agent in staving off the advance of muscle weakness. Here we review the molecular basis of muscle wasting associated with diseases, such as sarcopenia, muscular dystrophy and Amyotrophic Lateral Sclerosis, and discuss the potential therapeutic role of local IGF-1 isoforms in muscle aging and diseases.

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Related in: MedlinePlus

Model of stem cell-mediated muscle regeneration. (modified from ref. 18).                                            Muscle injury involves the activation of satellite cells and the                                            recruitment of circulating stem cells, which when penetrating the muscle                                            compartment receive myogenic signals and may contribute to muscle                                            regeneration and repair. This process is enhanced by mIGF-1 expression. By                                            modulating the inflammatory response and reducing fibrosis, supplemental                                            mIGF-1 creates a qualitatively different environment for sustaining more                                            efficient muscle regeneration and repair.
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Figure 2: Model of stem cell-mediated muscle regeneration. (modified from ref. 18). Muscle injury involves the activation of satellite cells and the recruitment of circulating stem cells, which when penetrating the muscle compartment receive myogenic signals and may contribute to muscle regeneration and repair. This process is enhanced by mIGF-1 expression. By modulating the inflammatory response and reducing fibrosis, supplemental mIGF-1 creates a qualitatively different environment for sustaining more efficient muscle regeneration and repair.

Mentions: The increased muscle mass in mIGF-1 transgenic mice was associated with augmented force generation compared to age-matched wild type littermates [17]. Examination of two year-old animals revealed that whereas wild type mice underwent characteristic muscle atrophy, expression of the mIGF-1 transgene was protective against normal loss of muscle mass during senescence [17]. Over-expression of the mIGF-1 transgene also preserved the regenerative capacity of senescent muscle tissues stimulating both the activity of satellite cells and the recruitment of circulating stem cells [17,18] (Figure 2). We demonstrated that upon muscle injury, stem cells expressing c-Kit, Sca-1, and CD45 antigens increased locally and the percentage of the recruited cells were conspicuously enhanced by mIGF-1 expression [18]. More recently, we demonstrated that local expression of mIGF-1 accelerates the regenerative process of injured skeletal muscle, negatively modulating the inflammatory response [19]. These data indicate that mIGF-1 promote a qualitative environment, guaranteeing a more efficient muscle regeneration process. Thus mIGF-1 can overcome the normal inability of skeletal muscle to sustain regeneration and repair and as such represents a potentially effective gene therapeutic strategy to combat muscle wasting. This hypothesis was supported by the demonstration that the action of mIGF-1 is not dependent on life-long expression. Introduction of mIGF-1 somatically using an Adeno-Associated-Viral (AAV) vector was sufficient to rejuvenate the leg muscles of 27 month old mice, which exhibited the same mechanical force as legs of younger mice, and did not develop the pathological characteristics of senescent muscle [20].


Counteracting muscle wasting in aging and neuromuscular diseases: the critical role of IGF-1.

Scicchitano BM, Rizzuto E, MusarĂ² A - Aging (Albany NY) (2009)

Model of stem cell-mediated muscle regeneration. (modified from ref. 18).                                            Muscle injury involves the activation of satellite cells and the                                            recruitment of circulating stem cells, which when penetrating the muscle                                            compartment receive myogenic signals and may contribute to muscle                                            regeneration and repair. This process is enhanced by mIGF-1 expression. By                                            modulating the inflammatory response and reducing fibrosis, supplemental                                            mIGF-1 creates a qualitatively different environment for sustaining more                                            efficient muscle regeneration and repair.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2806025&req=5

Figure 2: Model of stem cell-mediated muscle regeneration. (modified from ref. 18). Muscle injury involves the activation of satellite cells and the recruitment of circulating stem cells, which when penetrating the muscle compartment receive myogenic signals and may contribute to muscle regeneration and repair. This process is enhanced by mIGF-1 expression. By modulating the inflammatory response and reducing fibrosis, supplemental mIGF-1 creates a qualitatively different environment for sustaining more efficient muscle regeneration and repair.
Mentions: The increased muscle mass in mIGF-1 transgenic mice was associated with augmented force generation compared to age-matched wild type littermates [17]. Examination of two year-old animals revealed that whereas wild type mice underwent characteristic muscle atrophy, expression of the mIGF-1 transgene was protective against normal loss of muscle mass during senescence [17]. Over-expression of the mIGF-1 transgene also preserved the regenerative capacity of senescent muscle tissues stimulating both the activity of satellite cells and the recruitment of circulating stem cells [17,18] (Figure 2). We demonstrated that upon muscle injury, stem cells expressing c-Kit, Sca-1, and CD45 antigens increased locally and the percentage of the recruited cells were conspicuously enhanced by mIGF-1 expression [18]. More recently, we demonstrated that local expression of mIGF-1 accelerates the regenerative process of injured skeletal muscle, negatively modulating the inflammatory response [19]. These data indicate that mIGF-1 promote a qualitative environment, guaranteeing a more efficient muscle regeneration process. Thus mIGF-1 can overcome the normal inability of skeletal muscle to sustain regeneration and repair and as such represents a potentially effective gene therapeutic strategy to combat muscle wasting. This hypothesis was supported by the demonstration that the action of mIGF-1 is not dependent on life-long expression. Introduction of mIGF-1 somatically using an Adeno-Associated-Viral (AAV) vector was sufficient to rejuvenate the leg muscles of 27 month old mice, which exhibited the same mechanical force as legs of younger mice, and did not develop the pathological characteristics of senescent muscle [20].

Bottom Line: Most muscle pathologies are characterized by the progressive loss of muscle tissue due to chronic degeneration combined with the inability of regeneration machinery to replace the damaged muscle.Among them, insulin-like growth factor-1 (IGF-1) has been implicated in the control of skeletal muscle growth, differentiation, survival, and regeneration and has been considered a promising therapeutic agent in staving off the advance of muscle weakness.Here we review the molecular basis of muscle wasting associated with diseases, such as sarcopenia, muscular dystrophy and Amyotrophic Lateral Sclerosis, and discuss the potential therapeutic role of local IGF-1 isoforms in muscle aging and diseases.

View Article: PubMed Central - PubMed

Affiliation: Institute Pasteur Cenci-Bolognetti, Department of Histology and Medical Embryology, IIM, Sapienza University of Rome, Rome 00161, Italy.

ABSTRACT
Most muscle pathologies are characterized by the progressive loss of muscle tissue due to chronic degeneration combined with the inability of regeneration machinery to replace the damaged muscle. These pathological changes, known as muscle wasting, can be attributed to the activation of several proteolytic systems, such as calpain, ubiquitin-proteasome and caspases, and to the alteration in muscle growth factors. Among them, insulin-like growth factor-1 (IGF-1) has been implicated in the control of skeletal muscle growth, differentiation, survival, and regeneration and has been considered a promising therapeutic agent in staving off the advance of muscle weakness. Here we review the molecular basis of muscle wasting associated with diseases, such as sarcopenia, muscular dystrophy and Amyotrophic Lateral Sclerosis, and discuss the potential therapeutic role of local IGF-1 isoforms in muscle aging and diseases.

Show MeSH
Related in: MedlinePlus