In skeletal muscle, interactions between contractile and connective tissue elements at multiple scales result in emergent properties that determine mechanical performance. One of these phenomena is architectural gearing, which is quantified as the ratio of muscle velocity to muscle fiber velocity. Many pennate muscles operate with a gear ratio greater than one because muscles shorten through a combination of muscle fiber shortening and fiber rotation. Within a muscle, gearing is variable across contractions. During low force contractions, muscles operate at high gear while muscles operate at low gear during high force contractions. This variable gearing has a significant impact on muscle performance as muscle architectural changes favor muscle speed during fast contractions and muscle force during slow, high force contractions. We hypothesize that gearing in any given contraction is determined by the dynamic interaction of fiber-generated forces, fluid force transmission, and the elastic behavior of intramuscular connective tissues. Because muscle is isovolumetric, muscle fibers must bulge radially when they shorten. Radial bulging and fiber-generated forces off-axis from the muscle line of action exert forces that load connective tissues that ensheath fibers, fascicles, and the whole muscle. The way in which fluid pressures and fiber forces interact to load connective tissues in three-dimensions remains poorly understood because of the complex and multiscale nature of these interactions. Here we review evidence for variable gearing in pennate muscles, present a conceptual model that describes the fundamental interactions that determine gearing, and discuss where gaps remain in our understanding of the determinants and consequences of muscle shape change and variable gearing.

Skeletal muscles power a broad diversity of animal movements, despite only being able to produce high forces over a limited range of velocities. Pennate muscles use a range of gear ratios, the ratio of muscle shortening velocity to fiber shortening velocity, to partially circumvent these force-velocity constraints. Muscles operate with a high gear ratio at low forces; fibers rotate to greater angles of pennation, enhancing velocity but compromising force. At higher forces, muscles operate with a lower gear ratio; fibers rotate little so limiting muscle shortening velocity, but helping to preserve force. This ability to shift gears is thought to be due to the interplay of contractile force and connective tissue constraints. In order to test this hypothesis, gear ratios were determined in the medial gastrocnemius muscles of both healthy young rats, and old rats where the interaction between contractile and connective tissue properties was assumed to be disrupted. Muscle fiber and aponeurosis stiffness increased with age (P<0.05) from 19.1±5.0 kPa and 188.5±24.2 MPa, respectively, in young rats to 39.1±4.2 kPa and 328.0±48.3 MPa in old rats, indicating a mechanical change in the interaction between contractile and connective tissues. Gear ratio decreased with increasing force in young (P<0.001) but not old (P=0.72) muscles, indicating that variable gearing is lost in old muscle. These findings support the hypothesis that variable gearing results from the interaction between contractile and connective tissues and suggest novel explanations for the decline in muscle performance with age.

A growing body of research on the mechanics and energetics of terrestrial locomotion has demonstrated that elastic elements acting in series with contracting muscle are critical components of sustained, stable and efficient gait. Far fewer studies have examined how the nervous system modulates muscle-tendon interaction dynamics to optimize 'tuning' or meet varying locomotor demands. To explore the fundamental neuromechanical rules that govern the interactions between series elastic elements (SEEs) and contractile elements (CEs) within a compliant muscle-tendon unit (MTU), we used a novel work loop approach that included implanted sonomicrometry crystals along muscle fascicles. This enabled us to decouple CE and SEE length trajectories when cyclic strain patterns were applied to an isolated plantaris MTU from the bullfrog (Lithobates catesbeianus). Using this approach, we demonstrate that the onset timing of muscle stimulation (i.e. stimulation phase) that involves a symmetrical MTU stretch-shorten cycle during active force production results in net zero mechanical power output, and maximal decoupling of CE and MTU length trajectories. We found it difficult to 'tune' the muscle-tendon system for strut-like isometric force production by adjusting stimulation phase only, as the zero power output condition involved significant positive and negative mechanical work by the CE. A simple neural mechanism - adjusting muscle stimulation phase - could shift an MTU from performing net zero to net positive (energy producing) or net negative (energy absorbing) mechanical work under conditions of changing locomotor demand. Finally, we show that modifications to the classical work loop paradigm better represent in vivo muscle-tendon function during locomotion.

Aponeuroses are sheet-like elastic tendon structures that cover a portion of the muscle belly and act as insertion sites for muscle fibers while free tendons connect muscles to bones. During shortening contractions, free tendons are loaded in tension and lengthen due to the force acting longitudinally along the muscle׳s line of action. In contrast, aponeuroses increase in length and width, suggesting that aponeuroses are loaded in directions along and orthogonal to the muscle׳s line of action. Because muscle fibers are isovolumetric, they must expand radially as they shorten, potentially generating a force that increases aponeurosis width. We hypothesized that increases in aponeurosis width result from radial expansion of shortening muscle fibers. We tested this hypothesis by combining in situ muscle-tendon measurements with high-speed biplanar fluoroscopy measurements of the turkey׳s lateral gastrocnemius (n=6) at varying levels of isotonic muscle contractions. The change in aponeurosis width during periods of constant force depended on both the amount of muscle shortening and the magnitude of force production. At low to intermediate forces, aponeurosis width increased in direct proportion to fiber shortening. At high forces, aponeurosis width increased to a lesser extent or in some cases, decreased slightly during fiber shortening. Our results demonstrate that forces generated from radial expansion of shortening muscle fibers tend to drive increases in aponeurosis width, whereas longitudinal forces tend to decrease aponeurosis width. Ultimately, it is these two opposing forces that drive changes in aponeurosis width and alter series elastic stiffness during a muscle contraction.

Background

Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally.

Methods

The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented.

Findings

Globally, in 2019, the risk factors included in this analysis accounted for 4·45 million (95% uncertainty interval 4·01-4·94) deaths and 105 million (95·0-116) DALYs for both sexes combined, representing 44·4% (41·3-48·4) of all cancer deaths and 42·0% (39·1-45·6) of all DALYs. There were 2·88 million (2·60-3·18) risk-attributable cancer deaths in males (50·6% [47·8-54·1] of all male cancer deaths) and 1·58 million (1·36-1·84) risk-attributable cancer deaths in females (36·3% [32·5-41·3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20·4% (12·6-28·4) and DALYs by 16·8% (8·8-25·0), with the greatest percentage increase in metabolic risks (34·7% [27·9-42·8] and 33·3% [25·8-42·0]).

Interpretation

The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden.

Funding

Bill & Melinda Gates Foundation.