the dominant role in muscle homeostasis and regeneration is played by satellite cells , which reside between the basal lamina and sarcolemma of myofibers . satellite cells can be activated in response to both physiological stimuli , such as exercise , and under pathological conditions , such as injury and degenerative diseases , to generate a committed population of myoblasts that are capable of fusion and differentiation . satellite cells are able to fuse with existing myofibers , repairing damaged muscle fibers , or alternatively fuse to each other to form new myofibers . rt - pcr analysis , gene targeting strategies , and molecular imaging revealed that satellite cells present a heterogeneous profile of gene expression depending on the functional stage of the myogenic program . it has been reported that quiescent satellite cells express several relevant markers such as c - met , m - cadherin , foxk , pax-7 , ncam , syndecan 3 and 4 , cd34 , caveolin-1 , sox 8 , sox 15 , and vcam-1 ( figure 1b ) . pax3 , the paralog ( pair of genes that derive from the same ancestral gene ) of pax7 , is also expressed in quiescent muscle satellite cells in a subset of muscles and it plays an important role in regulating the entry of satellite cells into the myogenic programme . once activated , satellite cells up - regulate c - met , pax-7 , and m - cadherin and activate the expression factors involved in the specification of the myogenic program such as myf-5 and myod ( figure 1b ) . the activated satellite cells proliferate as indicated by the expression of factors involved in cell cycle progression ( figure 1b )   and by incorporation of brdu and [ 3h ] thimidine . ultimately the committed satellite cells fuse each other , or to the existing fibers , to form new muscle fibers , which are characterized by small size and by the expression of the embryonic / neonatal isoform of myhc ( figure 1b ) . stem cell populations can participate to muscle regeneration , contributing to maintain the pool of satellite cells . these stem cell populations could either reside within muscle , or recruited via circulation in response to homing signals secreted by injured skeletal muscle . these populations include endothelial - associated cells , interstitial cells , and bone marrow - derived cells . at first sight the origin of non muscle - derived stem cells appears to be mainly restricted to the hemo - vascular system ( hematopoietic , endothelial , pericytes ) . a question relevant to muscle regeneration is whether there is any lineage relationship between one or more types of mesoderm stem cells and muscle satellite cells . although there is not a conclusive answer to this question , it is possible that any of these cells may leave the vessel wall , enter the interstitial space and produce factors that stimulate the activity of satellite cells . one of the critical points that remain to be addressed is the following : if skeletal muscle possesses a stem cell compartment , it is not clear why skeletal muscle fails to regenerate under pathological conditions . either the resident muscle stem cells drastically decrease during aging and in several degenerative diseases or perhaps the pathological muscle is a prohibitive environment for stem cells activation and function . although we lack definitive answers , several evidences suggested that with age or under pathological conditions , the systemic environment impinges the activity of satellite cells and stimulates fibrotic accumulation . in particular , recent reports described the identification of muscle - derived interstitial cells , referred to as fibro - adipocyte progenitors ( faps ) . under physiologic regenerative stimuli , in contrast , in degenerating muscles , such as muscular dystrophy , these cells turn into fibro - adipocytes , which mediate fat deposition and fibrosis . the environmental niche that nurtures and maintains the stem cells at different anatomical sites and influences stem cell proliferation and differentiation represents a critical component of muscle regeneration . indeed , heterochronic experiments demonstrated that old muscle successfully regenerates when transplanted in a young animal , whereas the regeneration of young muscle transplanted in an old host was impaired . this hypothesis has been clearly validated by parabiotic experiments , the union of two organisms that share the circulatory system , demonstrating the rejuvenation of aged progenitor cells by exposure to a young systemic environment . similarly , we also demonstrated that human satellite cells fail to differentiate when cultured in isochronic conditions . immunofluorescence analysis for the expression of myhc revealed that aged satellite cells did not display major defect in the propensity to fuse when differentiated under standard conditions , namely in dmem supplemented with 5% horse serum . of note , we observed that autologous serum ( isochronic culture conditions ) dramatically reduced muscle differentiation , which was partially rescued when aged satellite cells were differentiated in heterologous/ heterochronic serum ( from young donors ) . these data suggest that with age , the systemic environment is less effective in maintaining the myogenic fate of muscle stem cells and , instead , facilitates conversion to a fibrogenic fate . the modifications with aging in the secretome of the different cell types present at different phases of regeneration is probably then crucial , as is expression of relevant cell surface receptors , which can also change with age . among potential factors , notch , wnt , and insulin - like growth factor-1 ( igf-1 ) notch signaling is one of the major pathway that regulates the activation and expansion of the satellite cell lineage during embryogenesis , and in the adult . the decline of notch signaling with age is thought to be one of the causes of the decreased regenerative potential of aged satellite cells . indeed forced activation of notch signaling in injured muscle of aged mice restores regenerative potential to that tissue . in addition , the temporal balance between notch and wnt signaling orchestrates the precise progression of muscle precursor cells along the myogenic lineage pathway , during postnatal myogenesis . nevertheless , the wnt signal must be finely modulated , since a persistence of wnt signal , as , for example , observed in aged mice , can be associated with an increase in tissue fibrosis . conversely , the myogenic - to - fibrogenic conversion has been abrogated by wnt inhibitors . among growth factors , insulin - like growth factor-1 ( igf-1 ) has been implicated in many anabolic pathways in skeletal muscle and it plays a central role during muscle regeneration . unlike other growth factors , the local isoform of igf-1 ( migf-1 ) also stimulates myogenic differentiation , generates a pronounced muscle hypertrophy , modulates the inflammatory response , and accelerates the functional rescue of injured skeletal muscle . in addition , we observed that forced expression of migf-1 improves muscle mass and strength , decreases myonecrosis , and reduces fibrosis in dystrophic mice . this is of particular relevance to the human dystrophic condition where virtually all skeletal muscles succumb to fibrosis . in addition we recently demonstrated that muscle - specific expression of migf-1 can counter aspects of the muscular dystrophy associated with the loss of dystrophin , modulating relevant molecules of the genetic and epigenetic circuitries in the mdx dystrophic mouse model . our work is consistent with a model in which overexpression of migf-1 confers robustness to dystrophic muscle , impedes the activation of a chronic inflammatory response , activates the circuitry of muscle differentiation and maturation . another study also demonstrated that co - injection of the raav - microdystrophin and raav - migf-1 vectors resulted in increased muscle mass and strength , reduced myofiber degeneration , and increased protection against contraction - induced injury . these results suggest that a combination of promoting muscle regenerative capacity and preventing muscle necrosis could be an effective treatment for the secondary symptoms caused by the primary loss of dystrophin . in addition , localized expression of migf-1 delays the onset and progression of disease in amyotrophic lateral sclerosis ( als ) mice , ameliorates muscle pathology and reduces motor neuron loss in a mouse model of spinal and bulbar muscular atrophy ( sbma ) , and improves muscle mass and extends the survival of severe spinal muscular atrophy ( sma ) mice . interestingly , we recently demonstrated that igf-1 isoforms are also up - regulated in senior patients treated with electrical stimulation ( es ) , promoting satellite cells activation , reduction in the expression of muscle - specific atrophy - related ubiquitin ligase genes , and promoting the remodeling of extracellular matrix . another potential factor that , similarly to igf-1 , plays important physiological roles in skeletal muscle development and homeostasis is the neurohypophyseal hormone vasopressin ( avp ) . in a recent study , we demonstrated that muscle - specific stimulation of avp induces acceleration of satellite cell activation and earlier stimulation of specific pathways involved in muscle regeneration . these findings demonstrate that while stem cells represent an important determinant for tissue regeneration , a  qualified thus , in several muscle pathologies the systemic environment is less effective in maintaining the myogenic fate of muscle stem cells and , instead , facilitates conversion to a fibrogenic fate . in this context , therapeutic applications of adult stem cells to aged or pathological tissue repair , in the context of regenerative medicine , will require an increased understanding of stem - cell biology , environment of pathological tissue and interaction between the two .