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Overuse injuries and trauma in tendon often involve acute or chronic pain and eventual matrix destruction. Anti-inflammatory drugs have been used as a treatment, however, the cellular and molecular mechanisms of the destructive processes in tendon are not clearly understood. It is thought that an inflammatory event may be involved as an initiating factor. Mediators of the inflammatory response include cytokines released from macrophages and monocytes. Interleukin-1 beta (IL-1 p) is a candidate proinflammatory cytokine that is active in connective tissues such as bone and cartilage. We hypothesized that tendon cells would express receptors and respond to IL-1 b in an initial "molecular inflammation" cascade, that is, connective tissue cell expression of cytokines that induce matrix destructive enzymes. This cascade results in expression of matrix metalloproteinases (MMPs) and aggrecanases that may lead to matrix destruction. Normal human tendon cells from six patients were isolated, grown to quiescence and treated with human recombinant IL-lP in serum-free medium for 16 h. Total RNA was isolated and mRNA expression assessed by semiquantitative RT-PCR. IL-lP (1 nM) induced mRNAs for cyclooxygenase 2 (COX2), MMP-I, -3, -13 and aggrecanase-1 as well as IL-1 j3 and IL-6, whereas mRNAs for COX1 and MMP-2 were expressed constitutively. The IL-lj3-treated tendon cells released prostaglandin E2 (PGE2) in the medium, suggesting that the inducible COX2 catalyzed this synthesis. Induction of PGE2 was detectable at 10 pM IL-1 j3. IL-10 also stimulated MMP-1 and -3 protein secretion. Induction of MMP-1 and -3 was detectable at 10 pM IL-1 fi. Post-injury or after some other inciting events, exogenous IL-1 P released upon bleeding or as leakage of local capillaries may drive a proinflammatory response at the connective tissue cell level. The resulting induction of COX2, MMP-1 and -3 may underscore a potential for nonlymphocyte-mediated cytokine production of MMPs that causes matrix destruction and a loss of tendon biomechanical properties. Endogenous IL-1 b might contribute to the process through a positive feedback loop by stimulating expression and accumulation of MMPs in the tendon matrix.

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The sliding filament and cross-bridge theories of muscle contraction provide discrete predictions of the tetanic force-length relationship of skeletal muscle that have been tested experimentally. The active force generated by a maximally activated single fiber (with sarcomere length control) is maximal when the filament overlap is optimized and is proportionally decreased when overlap is diminished. The force-length relationship is a static property of skeletal muscle and, therefore, it does not predict the consequences of dynamic contractions. Changes in sarcomere length during muscle contraction result in modulation of the active force that is not necessarily predicted by the cross-bridge theory. The results of in vivo studies of the force-length relationship suggest that muscles that operate on the ascending limb of the force-length relationship typically function in stretch-shortening cycle contractions, and muscles that operate on the descending limb typically function in shorten-stretch cycle contractions. The joint moments produced by a muscle depend on the moment arm and the sarcomere length of the muscle. Moment arm magnitude also affects the excursion (length change) of a muscle for a given change in joint angle, and the number of sarcomeres arranged in series within a muscle fiber determines the sarcomere length change associated with a given excursion.

For electrically stimulated muscles, it has been observed that maximal muscle force during and after stretch is substantially greater than the corresponding isometric force. However, this observation has not been made for human voluntary contractions. We investigated the effects of active muscle stretch on muscle force production for in vivo human adductor pollicis (n= 12) during maximal voluntary contractions and electrically induced contractions. Peak forces during stretch, steady‐state isometric forces following stretch, and passive forces following muscle deactivation were compared to the corresponding isometric forces obtained at optimal muscle length. Contractions with different stretch magnitudes (10, 20, and 30 deg at a constant speed of 10 deg s−1) and different speeds (10, 20, and 60 deg s−1 over a range of 30 deg) were performed in triplicate in a random order, balanced design. We found three novel results: (i) there was steady‐state force enhancement following stretch in voluntarily contracted muscles; (ii) some force enhancement persisted following relaxation of the muscle and (iii) force enhancement, for some stretch conditions, exceeded the maximum isometric force at optimal muscle length. We conclude from these results that voluntary muscle contraction produces similar force enhancement to that observed in the past with electrically stimulated preparations. Therefore, steady‐state force enhancement may play a role in everyday movements. Furthermore, these results suggest that non‐uniformities in sarcomere length do not, at least not exclusively, account for the force enhancement following active muscle stretch, and that the stretch magnitude‐dependent passive force enhancement observed here may be responsible for the enhancement of force above the isometric reference force at optimal muscle length.

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.

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