Читать книгу Musculoskeletal Disorders - Sean Gallagher - Страница 40

The origin of muscle fatigue (specifically, a progressive and reversible loss in the ability to produce the desired force) is complex. Muscle fatigue occurs along with physiological changes that reflect changes in the balance between muscular demand and vascular supply (Cote, 2014; Yang, Leitkam, & Cote, 2019). This latter imbalance has also been termed an “energy crisis” (Simons & Travell, 1981). Muscle fatigue can also arise with alterations in neuromuscular junctions, neurotransmitters released from peripheral nerves after tissue damage, and axonal neuropathy if compressive nerve injury develops (Zajac, Chalimoniuk, Maszczyk, Golas, & Lngfort, 2015). Chronic inflammation, which can occur after prolonged high demand tasks, has a direct deleterious effect on skeletal muscles, decreasing force and muscle quality. Persistent elevations of systemic tumor necrosis factor alpha (TNF‐α) is a primary endocrine stimulus for contractile dysfunction (Argiles, Campos, Lopez‐Pedrosa, Rueda, & Rodriguez‐Manas, 2016; Leal, Lopes, & Batista Jr., 2018; So, Kim, Kim, & Song, 2014). Dependent on the magnitude of mechanical myofiber damage, muscle strength can decline. Substantial muscle damage also induces myofiber apoptosis and a loss of muscle mass. Aging enhances muscle dysfunction due to age‐dependent increase in inflammatory responses and cell apoptosis and reduced repair mechanisms (Argiles et al., 2016). Additionally, the Cinderella Hypothesis of a hierarchical recruitment of smaller motor units disproportionately over larger units may provide insight into muscle fatigue (Enoka & Duchateau, 2008). In this hypothesis, the first recruited units are the smallest muscle units, which allow for the fine‐tuning of force applied during delicate tasks. These small motor units may also be the last to be relaxed during prolonged muscle contractions. Only as the load reaches the maximum values, larger units are recruited. Thus, the smaller fibers may be more susceptible to an energy crisis of muscle fatigue and pain signaling (Enoka & Duchateau, 2008).

Another cause of physiological muscle fatigue can be altered myocellular calcium [Ca²⁺] regulation, sarcoplasmic reticulum Ca²⁺ handling, and sarcoplasmic reticulum protein expression, all occurring as a result of chronic muscle overload, as summarized in Figure 2.7. (Allen et al., 2008; Hadrevi et al., 2019; Ortenblad et al., 2000). The process of controlling the production of force within the muscle, known as excitation–contraction–relaxation coupling, requires a tight regulation of the intracellular cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) in muscle enabling activation of the contractile apparatus, while protecting the cell from deleterious [Ca²⁺]_i overload. This is permitted through an instantaneous release of large amounts of Ca²⁺ through the sarcoplasmic reticulum Ca²⁺ release channel and ryanodine receptor (RyR), thereby increasing [Ca²⁺]_i and a subsequent, almost simultaneous reuptake of Ca²⁺ into the SR by the SR ATPases (SERCA) together with buffering of Ca²⁺ inside the sarcoplasmic reticulum by the protein calcequestrin (Casq1) (Berchtold, Brinkmeier, & Muntener, 2000; Ortenblad & Stephenson, 2003; Periasamy & Kalyanasundaram, 2007).

Figure 2.7 A model for possible early and late events in muscle response to a repetitive high repetition high force (HRHF) upper extremity task for 6 weeks. Exposure to the HRHF task induces an impaired muscle Ca²⁺ homeostasis, leading to an increase in [Ca²⁺]_i as indicated by an increase in pCalmodulin kinase (pCAM). The increased [Ca²⁺]_i may be mediated by leaky ryanodine receptor 1 (RyR1) with or without an uptake of extracellular Ca²⁺. Furthermore, HRHF induces muscle metabolic stress indicated by an increase in muscle heat shock protein 72 (Hsp72). The increased [Ca²⁺]_i is accompanied by an increased sarco/endoplasmic reticulum vesicle Ca²⁺ uptake rate and sarco/endoplasmic reticulum Ca²⁺‐ATPase (SERCA1) together with increased calcequestrin (Casq1), which may lead to an enhanced sarcoplasmic reticulum Ca²⁺ buffering capacity. The model points to an altered myocellular Ca²⁺ handling as an early adaptation to muscle overload.

Hadrevi, J., Barbe, M. F., Ortenblad, N., Frandsen, U., Boyle, E., Lazar, S., … Sogaard, K. (2019). Calcium fluxes in work‐related muscle disorder: Implications from a rat model. BioMed Research International, 2019, 5040818. doi:10.1155/2019/5040818 / Hindawi / CC BY‐4.0.

Muscle myalgia (i.e., muscle pain) is associated with muscle stiffness, weakness, and increased tension (Ohlsson, Attewell, Johnsson, Ahlm, & Skerfving, 1994). Like muscle fatigue, dysfunctional Ca²⁺ homeostasis has been implicated in skeletal muscles of patients suffering from chronic neck and shoulder pain (Hadrevi, Ghafouri, Larsson, Gerdle, & Hellström, 2013). A study of biopsied myalgic muscle from human subjects showed a decreased abundance of calcequestrin (Casq1) together with an increased abundance of sarco/endoplasmic reticulum Ca²⁺‐ATPase (SERCA1) (Hadrevi et al., 2016). This may indicate an increased uptake of Ca²⁺ into the sarcoplasmic reticulum, although with a reduced buffering capacity in that structure. Additionally, increased interstitial concentrations of inflammatory mediators, such as bradykinins, kallidin, lactate, pyruvate, and K⁺, have been found in patients with chronic severe trapezius myalgia (Gerdle et al., 2008; Gerdle et al., 2014). Injections of pro‐inflammatory cytokines such as tumor necrosis factor alpha have also been shown to increase muscle pain/myalgia by activating the firing of pain‐related nerve fibers (i.e., nociceptors) (Kehl, Trempe, & Hargreaves, 2000; Schafers, Sorkin, & Sommer, 2003).

Muscle fibrosis is also hypothesized to be a key factor in motor dysfunction, increased discomfort, and pain observed in patients with MSDs (Backman, Andersson, Wennstig, Forsgren, & Danielson, 2011; Barbe, Gallagher, & Popoff, 2013a; Barbe et al., 2013b; Stauber, 2004). Tissue fibrosis is thought to distort dynamic properties of tissue and contribute to functional declines perhaps due to adherence of adjacent structures or encapsulation of nerve related pain fibers (Driscoll & Blyum, 2011; Fisher et al., 2015; Pavan et al., 2014; Zugel et al., 2018). Fibrotic muscle changes may occur at any point in the musculotendinous unit including within the muscle fibers and at the musculotendinous junction (Abdelmagid et al., 2012; Fedorczyk et al., 2010; Fisher et al., 2015; Hilliard, Amin, Popoff, & Barbe, 2020). There are several possibilities for the continued increase in fibrogenic proteins (which include collagen, transforming growth factor beta 1 (TGF‐β1), and connective tissue growth factor/cell communication network factor 2 (CTGF/CCN2) and in the assembly and remodeling of the extracellular matrix with chronic overload or repeated injury, including (a) dysregulation of negative feedback loops and therefore continued translation of fibrogenic proteins from their mRNA; (b) upregulated export of important extracellular matrix proteins, like collagen, from the endoplasmic reticulum to the extracellular matrix; and (c) a shift in the balance between extracellular matrix assembly and degradation to favor the assembly of extracellular matrix.