The musculoskeletal system is significantly more complex than portrayed by traditional reductionist approaches that have focused on and studied the components of this system separately. While bone and skeletal muscle are the two largest tissues within this system, this system also includes tendons, ligaments, cartilage, joints and other connective tissue along with vascular and nervous tissue. Because the main function of this system is locomotion, the mechanical interaction among the major players of this system is essential for the many shapes and forms observed in vertebrates and even in invertebrates. Thus, it is logical that the mechanical coupling theories of musculoskeletal development exert a dominant influence on our understanding of the biology of the musculoskeletal system, because these relationships are relatively easy to observe, measure, and perturb. Certainly much less recognized is the molecular and biochemical interaction among the individual players of the musculoskeletal system. In this brief review article, we first introduce some of the key reasons why the mechanical coupling theory has dominated our view of bone-muscle interactions followed by summarizing evidence for the secretory nature of bones and muscles. Finally, a number of highly physiological questions that cannot be answered by the mechanical theories alone will be raised along with different lines of evidence that support both a genetic and a biochemical communication between bones and muscles. It is hoped that these discussions will stimulate new insights into this fertile and promising new way of defining the relationships between these closely related tissues. Understanding the cellular and molecular mechanisms responsible for biochemical communication between bone and muscle is important not only from a basic research perspective but also as a means to identify potential new therapies for bone and muscle diseases, especially for when they co-exist.
Most excitable cells maintain tight control of intracellular Ca(2+) through coordinated interaction between plasma membrane and endoplasmic or sarcoplasmic reticulum. Quiescent sarcoplasmic reticulum Ca(2+) release machinery is essential for the survival and normal function of skeletal muscle. Here we show that subtle membrane deformations induce Ca(2+) sparks in intact mammalian skeletal muscle. Spontaneous Ca(2+) sparks can be reversibly induced by osmotic shock, and participate in a normal physiological response to exercise. In dystrophic muscle with fragile membrane integrity, stress-induced Ca(2+) sparks are essentially irreversible. Moreover, moderate exercise in mdx muscle alters the Ca(2+) spark response. Thus, membrane-deformation-induced Ca(2+) sparks have an important role in physiological and pathophysiological regulation of Ca(2+) signalling, and uncontrolled Ca(2+) spark activity in connection with chronic activation of store-operated Ca(2+) entry may function as a dystrophic signal in mammalian skeletal muscle.
SUMMARY Exercise has beneficial effects on metabolism and on tissues. The exercise-induced muscle factor β-aminoisobutyric acid (BAIBA) plays a critical role in the browning of white fat and in insulin resistance. Here we show another function for BAIBA, that of a bone-protective factor that prevents osteocyte cell death induced by reactive oxygen species (ROS). L-BAIBA was as or more protective than estrogen or N-acetyl cysteine, signaling through the Mas-Related G Protein-Coupled Receptor Type D (MRGPRD) to prevent the breakdown of mitochondria due to ROS. BAIBA supplied in drinking water prevented bone loss and loss of muscle function in the murine hindlimb unloading model, a model of osteocyte apoptosis. The protective effect of BAIBA was lost with age, not due to loss of the muscle capacity to produce BAIBA but likely to reduced Mrgprd expression with aging. This has implications for understanding the attenuated effect of exercise on bone with aging.
The intracellular Ca 2+ ([Ca 2+ ] i ) level of skeletal muscles must be rapidly regulated during the excitation-contraction-relaxation process 1 . However, the signaling components involved in such rapid Ca 2+ movement are not fully understood. Here, we report that mice deficient in the novel phosphatidylinositol phosphate (PIP) phosphatase MIP displayed muscle weakness and fatigue. Muscles isolated from MIP −/− mice produced less contractile force, markedly prolonged relaxation, and exhibited exacerbated fatigue. Further analyses revealed that MIP deficiency resulted in spontaneous Ca 2+ leak from the internal store -the sarcoplasmic reticulum (SR). This was attributed to the decreased metabolism/dephosphorylation and the subsequent accumulation of MIP substrates, especially PI(3,5)P 2 and PI(3,4)P 2 . Furthermore, we found that PI(3,5)P 2 and PI(3,4)P 2 bound to and directly activated the Ca 2+ release channel/ryanodine receptor (RyR1) of the SR. These studies provide the first evidence that finely controlled PIP levels in muscle cells are essential for maintaining Ca 2+ homeostasis and muscle performance.During our systematic genome-wide survey for tyrosine/dual specificity phosphatases (unpublished work), we discovered a novel phosphatase by hidden Markov database mining using the conserved catalytic motif ([V/I][V/I]HCXXGXXR[T/S]) as the bait sequence. Both human (BC035690) and mouse (BC018294) homologies were identified. They share 90% identity in amino acid sequences ( Supplementary Information, Fig. S1). Northern blotting analyses illustrated that this phosphatase was predominantly expressed in skeletal muscle and heart (Fig. 1a). Immunostaining indicates that it is primarily localized in the cytoplasm (data not shown). To verify its phosphatase property, we generated a GST fusion protein and tested its catalytic activity using pNPP (p-Nitrophenyl Phosphate), a widely used non-specific 7Correspondence should be addressed to: C.K.Q. (e-mail: E-mail: cxq6@case.edu). 6 These authors contributed equally to this work. AUTHOR CONTRIBUTIONSJ.S., W.M. Y., M.B., J.A.S., and C.S. conducted the research and summarized the data. C.K.Q., M.B., H.H.V., T.M.N., and C.G. designed the experiments and wrote the manuscript. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests. (Fig. 1b). Instead, it dephosphorylated a variety of PIPs, especially PI(3,5) P 2 (Fig. 1c), similar to PTEN and myotubularin and myopathy related (MTMR) phosphatases that also favor PIPs as substrates despite containing tyrosine phosphatase domains 2 . As this new phosphatase is mainly expressed in skeletal muscle and heart, we named it MIP (musclespecific inositol phosphatase). While our gene knockout work on MIP was ongoing, the Mustalin group also identified this phosphatase (FLJ20133) in their comprehensive collection of tyrosine phosphatases from the human genome and listed it as the 14 th member of the MTMR family (MTMR14) based on the homology of its catalytic motif to myotubularin 3 . More recently, ina...
Ca 2þ -triggered membrane fusion, the defining step of exocytosis, enables temporal/spatial control over the release of biologically active compounds. The mechanism by which Ca 2þ triggers and modulates native membrane fusion is still poorly understood. As an unbiased approach to investigating this process, the effects of several thiol-reactive reagents on the homotypic fusion of isolated cortical vesicles (a stage-specific preparation for analyses of native Ca 2þ -triggered fusion) have been characterized. Such reagents have been consistently shown to inhibit the Ca 2þ -sensitivity, rate and extent of triggered fusion. However, we recently showed that iodoacetamide can also potentiate the Ca 2þ -sensitivity and rate of release [1]. This implicates two distinct thiol sites in the fusion process -one involved in the ability of vesicles to fuse (extent) and one that modulates fusion efficiency (Ca 2þ -sensitivity and kinetics). Capitalizing on this potentiating effect, we have now identified other fluorescent thiol-reactive reagents with similar effects: treatment with Lucifer yellow iodoacetamide, monobromobimane or dibromobimane resulted in an average leftward shift in EC 50 from 17.251.6mM to 8.951.9mM [Ca 2þ ] free . These fluorescent reagents can be used to enhance fusion and label proteins involved in the Ca 2þ -sensing mechanism. The lipid matrix at or near the fusion site can also modulate the fusion process, specifically via cholesterol-and sphingomyelin-enrichment that is thought to regulate the Ca 2þsensitivity and rate of fusion through spatial organization of critical lipids and proteins [2,3]. Proteins involved in Ca 2þ -sensing are thus likely to be situated within such areas of the membrane. Isolation of fluorescently labeled proteins from cholesterol-enriched vesicle membrane fractions by 2-dimesional electrophoresis is now being used to identify proteins potentially involved in the Ca 2þ -triggering steps of membrane fusion.
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