SKM and bone's morpho-functional unit are uniquely interconnected, so that every function of one organ depends on the other. The concept that bone and skeletal muscle form a morpho-functional unit was gradually developed and substantiated by scientific research during the latter half of the 20th century (Moss and Salentijn, 1969). Several pieces of evidence were brought in favor of this hypothesis (Tagliaferri et al., 2015), and all of them highlighted a high degree of co-variability in SKM and bone during all life stages. Studies on bed rest, immobilization, space flights and microgravity have depicted the strict co-modification of bone and muscle (Tagliaferri et al., 2015). As a result of this interaction, dysfunction in one of the two organs likely determines a parallel dysfunction in the other. In humans, during aging, bone loss, which may lead to osteopenia/osteoporosis and increased fracture risk, is associated with SKM mass loss, which may lead to sarcopenia; also, sarcopenia almost coexists with osteopenia/osteoporosis (Kirk et al., 2019). Exposure to nutritional or environmental factors during fetal life adversely affects musculoskeletal components and muscle-skeletal apparatus (Young et al., 2022b). In the growing subject, bone and muscle mass are strikingly correlated and strongly affected by physical activity (PA). While sedentary behavior is associated with low peak bone mass and SKM mass acquisition during puberty, a physically active behavior is associated with improved musculoskeletal mass and function in adulthood. This is particularly true in the case of weight-bearing and/or odd-impact activities (Xu et al., 2016).

Going deeper into the bone-muscle unit, the most evident connection is mechanical. SKMs attach to the bones by mediating the tendons and the muscle-tendinous junction (MTJ) (Fig. 1). Moving from the muscle through the MTJ to the tendon and then to the bone, the morpho-anatomical changes determine a continuum that parallels every structure's functional shift. However, the bone-muscle unit relies on a shared developmental/genetic background and a dense network of endocrine-like signals that imply an incredibly complex crosstalk between these two organs (Tagliaferri et al., 2015).

Bone and SKM share a common ontogenesis in mesenchymal tissues that develop together from the same embryological precursor during embryonic and fetal life (Cohen and Chen, 2008).

Bone and SKM formation begins in the embryonic development, driven by genes such as homeobox genes (Hoxes), nuclear factor kappa B (NF-κB), Wnt/β-catenin, transforming growth factor (TGF)β, bone morphogenetic proteins (BMPs), and fibroblast growth factors (FGFs), with mutations in these genes affecting development (Felsenthal and Zelzer, 2017; Song et al., 2019). Skeletogenesis starts from cartilage anlagen through vascularized growth plates, leading to synovial joint formation. Differentiating SKM cells contact developing bone, fuse, and form tendons that connect SKM and bone. Tendon genesis includes structures like the MTJ and tendon-bone bond, regulated by gradients of factors from both tissues. This structure undergoes innervation with the formation of neuromuscular junctions, followed by the embryo's initial movements. Bone morphology is refined by mechanical forces and muscle attachments, which influence the recruitment and differentiation of mesenchymal stem cells (MSCs) during development (Blitz et al., 2013; Suzue, 1996). The last aspect concerning SKM and bone connection is the endocrine relation, which concurs with increasing this unit's complexity. Indeed, both bone and muscle are secretory organs. Bone secretory function is ideally linked to the osteoblastic synthesis and release into the extracellular space of components of the extracellular matrix (ECM) that undergo mineralization (Lin et al., 2020). Most of the endocrine-like functions of bone are related to the coupling between bone formation and resorption and orchestrate the interaction between osteoblasts, the bone-forming cells, osteoclasts, the monocyte-derived bone-resorbing cells, and osteocytes, a further differentiation step from the osteoblast, responsible for mechanosensing. However, bone cells secrete molecules with extra-skeletal activity, the final scope of which is indirectly regulating bone metabolism and dynamics. The bioactive compounds released by bone cells as a consequence of stimulation (e.g., mechanical, hormonal, inflammatory) are named osteokines. On the other hand, SKM is well recognized as a secretory organ. However, unlike bone, the secreted species are only minimally involved in ECM organization while primarily devoted to autocrine (on the same cell that produces them), paracrine (on nearby cells), and endocrine (on distant cells via the bloodstream) signals (Kirk et al., 2020). During contractile activity—or in association with it—SKM cells express hundreds of compounds, known as myokines, that, once secreted, act on the same cell of origin, on neighboring cells, on SKM cells far from the cell source and on different cell types (Severinsen and Pedersen, 2020b). Most of the signals released by both bone and SKM are aimed at regulating the usage of the energy substrates, as the energy demand of these tissues is very high, even at rest (Kirk et al., 2020).

Having established the significance of mechanical coupling between bone and muscle and its pivotal role in developmental processes, we now shift our focus to the critical biochemical and endocrine dimensions of this interplay. A thorough understanding of these signaling pathways at the molecular level—including the functions of myokines, osteokines, and miRNAs—is crucial for deciphering the intricate regulation of musculoskeletal physiology and pathology, thereby providing valuable insights for therapeutic interventions. Although many studies have explored individual aspects of muscle–bone interaction, such as mechanical loading or myokine signaling (Dong et al., 2024; Kaji, 2024), especially in aging conditions (He et al., 2020; Li et al., 2019; Sheng et al., 2023) an integrated molecular perspective that includes mechanical, endocrine, and miRNA-mediated pathways is still lacking. This review seeks to fill that gap. This work delves into the structural and functional components of the bone-skeletal muscle morphofunctional unit, alongside associated pathophysiological states. It explores the molecular networks that govern biomechanics and the endocrine-like crosstalk between bone and skeletal muscle, offering a comprehensive summary of the current state of research in this domain.