For the past half century, the sliding filament-based cross-bridge theory has been the cornerstone of our understanding of how muscles contract. According to this theory, active force can only occur if there is overlap between the contractile filaments, actin and myosin. Otherwise, forces are thought to be caused by passive structural elements and are assumed to vary solely because of the length of the muscle. We observed increases in muscle force by a factor of 3 to 4 above the purely passive forces for activated and stretched myofibrils in the absence of actin-myosin overlap. We show that this dramatic increase in force is crucially dependent on the presence of the structural protein titin, cannot be explained with calcium activation, and is regulated by actin-myosin-based cross-bridge forces before stretching. We conclude from these observations that titin is a strong regulator of muscle force and propose that this regulation is based on cross-bridge force-dependent titin-actin interactions. These results suggest a mechanism for stability of sarcomeres on the "inherently unstable" descending limb of the force-length relationship, and they further provide an explanation for the protection of muscles against stretch-induced muscle injuries.

Increased OA in DIO animals is associated with greater body fat, not body mass. The link between gut microbiota and adiposity-derived inflammation and metabolic OA warrants further investigation.

Inflammation can arise in response to a variety of stimuli, including infectious agents, tissue injury, autoimmune diseases, and obesity. Some of these responses are acute and resolve, while others become chronic and exert a sustained impact on the host, systemically, or locally. Obesity is now recognized as a chronic low-grade, systemic inflammatory state that predisposes to other chronic conditions including metabolic syndrome (MetS). Although obesity has received considerable attention regarding its pathophysiological link to chronic cardiovascular conditions and type 2 diabetes, the musculoskeletal (MSK) complications (i.e., muscle, bone, tendon, and joints) that result from obesity-associated metabolic disturbances are less frequently interrogated. As musculoskeletal diseases can lead to the worsening of MetS, this underscores the imminent need to understand the cause and effect relations between the two, and the convergence between inflammatory pathways that contribute to MSK damage. Muscle mass is a key predictor of longevity in older adults, and obesity-induced sarcopenia is a significant risk factor for adverse health outcomes. Muscle is highly plastic, undergoes regular remodeling, and is responsible for the majority of total body glucose utilization, which when impaired leads to insulin resistance. Furthermore, impaired muscle integrity, defined as persistent muscle loss, intramuscular lipid accumulation, or connective tissue deposition, is a hallmark of metabolic dysfunction. In fact, many common inflammatory pathways have been implicated in the pathogenesis of the interrelated tissues of the musculoskeletal system (e.g., tendinopathy, osteoporosis, and osteoarthritis). Despite these similarities, these diseases are rarely evaluated in a comprehensive manner. The aim of this review is to summarize the common pathways that lead to musculoskeletal damage and disease that result from and contribute to MetS. We propose the overarching hypothesis that there is a central role for muscle damage with chronic exposure to an obesity-inducing diet. The inflammatory consequence of diet and muscle dysregulation can result in dysregulated tissue repair and an imbalance toward negative adaptation, resulting in regulatory failure and other musculoskeletal tissue damage. The commonalities support the conclusion that musculoskeletal pathology with MetS should be evaluated in a comprehensive and integrated manner to understand risk for other MSK-related conditions. Implications for conservative management strategies to regulate MetS are discussed, as are future research opportunities.

The sliding filament theory of muscle contraction is widely accepted as the means by which muscles generate force during activation. Within the constraints of this theory, isometric, steady-state force produced during muscle activation is proportional to the amount of filament overlap. Previous studies from our laboratory demonstrated enhanced titin-based force in myofibrils that were actively stretched to lengths which exceeded filament overlap. This observation cannot be explained by the sliding filament theory. The aim of the present study was to further investigate the enhanced state of titin during active stretch. Specifically, we confirm that this enhanced state of force is observed in a mouse model and quantify the contribution of calcium to this force. Titin-based force was increased by up to four times that of passive force during active stretch of isolated myofibrils. Enhanced titin-based force has now been demonstrated in two distinct animal models, suggesting that modulation of titin-based force during active stretch is an inherent property of skeletal muscle. Our results also demonstrated that 15% of the enhanced state of titin can be attributed to direct calcium effects on the protein, presumably a stiffening of the protein upon calcium binding to the E-rich region of the PEVK segment and selected Ig domain segments. We suggest that the remaining unexplained 85% of this extra force results from titin binding to the thin filament. With this enhanced force confirmed in the mouse model, future studies will aim to elucidate the proposed titin-thin filament interaction in actively stretched sarcomeres.

In contrast to isometric and shortening contractions, many observations made on actively lengthening muscles cannot be readily explained with the sliding filament and cross-bridge theory. Specifically, residual force enhancement, the persistent increase in force following active muscle lengthening, beyond what one would expect based on muscle length, has not been explained satisfactorily. Here, we summarize the experimental evidence on residual force enhancement, critically evaluate proposed mechanisms for the residual force enhancement, and propose a mechanism for residual force enhancement that explains all currently agreed upon experimental observations. The proposed mechanism is based on the engagement of the structural protein titin upon muscle activation and an increase in titin's resistance to active compared with passive stretching. This change in resistance from the passive to the active state is suggested to be based on 1) calcium binding by titin upon activation, 2) binding of titin to actin upon activation, and 3) as a consequence of titin-actin binding--a shift toward stiffer titin segments that are used in active compared with passive muscle elongation. Although there is some experimental evidence for the proposed mechanism, it must be stressed that much of the details proposed here remain unclear and should provide ample research opportunities for scientists in the future. Nevertheless, the proposed mechanism for residual force enhancement explains all basic findings in this area of research.

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It has been accepted for half a century that, for a given level of activation, the steady-state isometric force of a muscle sarcomere depends exclusively on the amount of overlap between the contractile filaments actin and myosin, or equivalently sarcomere length (Gordon AM et al., J Physiol 184: 170 -192, 1966). Moreover, according to the generally accepted paradigm of muscle contraction, the cross-bridge theory (Huxley AF, Prog Biophys Biophys Chem 7: 255-318, 1957), this steady-state isometric sarcomere force is independent of the muscle's contractile history (Huxley AF, Prog Biophys Biophys Chem 7: 255-318, 1957; Walcott S and Herzog W, Math Biosci 216: 172-186, 2008); i.e., it is independent of whether a muscle is held at a constant length before and during the contraction or whether the muscle is shortened or lengthened to the same constant length. This, however, is not the case, as muscles and single fibers that are stretched show greatly increased steady-state isometric forces compared with preparations that are held at a constant length (Abbott BC and Aubert XM,